Drug development is a process of bringing a new pharmaceutical drug to the market once a lead compound has been identified through the process of drug discovery. The drug development process starts from drug discovery to getting market approval and post-marketing studies.
This entire process of medical device/drug development takes years and completely depends on many of the factors such as
- Type of innovation – new drug or new treatment
- Type and category of drug – a simple drug, medical device, a complicated molecule or class III/IV medical device
- Type of development strategy applied and pathway chosen
- Countries choose to market, regulatory requirements, and evaluation timelines.
After a successful molecule identification, sponsors typically determine the goals and plan an optimized and clear step of events to move forward called “development strategy”. This plays a key role in achieving the goals in a smarter and efficient way to reach the market without deviation and delay.
After a successful drug discovery and attaining an NCE (New Chemical Entity) status, the process is complex and can be broadly divided into the following steps
- Pre-clinical development
- Clinical development
- Marketing approval
- Postmarketing studies
Preclinical development, also named as preclinical studies or nonclinical studies, is a stage of research that begins before clinical trials begin, and during which important feasibility, iterative testing, and drug safety data are collected, typically by testing in the laboratory.
The preclinical drug development strategy completely depends on the
- type of substance,
- category to which it belongs,
- the chosen animal model
- the primary treatment goal,
- sufficient quality data generation.
In pre-clinical trials, the drugs may undergo pharmacodynamics (PD), pharmacokinetics (PK), ADME, and toxicology testing.
- This allows researchers to allometrically estimate a safe starting dose of the drug for clinical trials in humans.
- Medical devices that do not have drugs attached will not undergo these additional tests and may go directly to Good Laboratory Practices (GLP) testing for the safety of the device and its components and
- Some medical devices will also undergo biocompatibility testing which helps to show whether a component of the device or all components are sustainable in a living model.
The regulators like the FDA require researchers to use Good Laboratory Practices (GLP), defined in medical product development regulations, for preclinical laboratory studies. These regulations set the minimum basic requirements for
- study conduct
- written protocols
- operating procedures
- study reports, and
- a system of quality assurance oversight for each study to help assure the safety of FDA-regulated product
Strategically, the pre-clinical studies shall follow the international guidelines for quality data generation and global acceptance.
Important points that are to be considered in the pre-clinical development
- Determine the goals of the pre-clinical stage before you even start the process
- Determine the timeline, budget estimate for the process, and set out the necessary ethical permissions
- Are the methods, animal species chosen apt for your goals?
- Are the guidelines chosen acceptable globally?
- Does the portfolio cover all the required tests and do not include un-necessary processes?
- Does the pre-clinical data generate provides a clear path for human trials?
- Do you have a scale-up the manufacturing process strategy (from milligram to kilogram and tonne) along with formulation development (CMC)
Preclinical studies don’t take a longer duration. However, these studies must provide detailed information on dosing and toxicity levels.
- After preclinical testing, researchers review their findings and decide whether the drug should be tested in people.
- The information gathered from this preclinical testing, and CMC, are submitted to regulatory authorities (in the US, to the FDA), as an Investigational New Drug (IND) application or any other regulatory.
- If the IND is approved, development moves to the clinical phase.
After a successful pre-clinical stage in animals, the next step is the clinical trials in humans.
- Clinical trials typically generate data on safety and efficacy
- They are conducted only after receiving health authority/ethics committee approval in the country
- These authorities are responsible for weighing the risk/benefit ratio of the trial.
Designing clinical trials
Researchers design clinical trials to answer specific research questions related to a medical product. These trials follow a specific study plan, called a protocol, that is developed by the researcher or manufacturer.
Before a clinical trial begins, researchers review prior information about the drug to develop research questions and objectives. Then, they decide
- Who qualifies to participate (selection criteria)
- How many people will be part of the study
- How long the study will last
- Whether there will be a control group and other ways to limit research bias
- How the drug will be given to patients and at what dosage
- What assessments will be conducted, when, and what data will be collected
- How the data will be reviewed and analyzed
Based on the substance under research trials are divided into
- Clinical trials for drugs/biologics
- Trials for drugs are conducted to find the safety and efficacy of a drug, compare with existing treatments, bio/availability and bio-equivalence studies, etc
- Clinical trials for medical devices
- Medical devices manufacturers are required to conduct clinical trials for market approval applications.
- Medical device trials may compare a new device to an established therapy or may compare similar devices to each other.
- Clinical trials for procedures
- New medical procedures may be subject to clinical trials
Clinical trials are further classified based upon the purpose
- Prevention trials look for ways to prevent disease in people who have never had the disease or to prevent a disease from returning. These approaches are done mainly for drugs such as vitamins, or other micronutrients, vaccines, or lifestyle changes.
- Diagnostic trials are conducted to find better tests or procedures for diagnosing a particular disease or condition.
- Screening trials test for ways to identify certain diseases or health conditions.
- Treatment trials test experimental drugs, new combinations of drugs, or new approaches to surgery or radiation therapy.
- Genetic trials are conducted to assess the prediction accuracy of genetic disorders making a person more or less likely to develop a disease.
- Quality of life trials (supportive care trials) evaluates how to improve comfort and quality of care for people with a chronic illness.
- Epidemiological trials have the goal of identifying the general causes, patterns, or control of diseases in large numbers of people.
- Compassionate use trials or expanded access trials provide partially tested, unapproved therapeutics to a small number of patients who have no other realistic options. and this involves a disease for which no effective therapy has been approved or a patient who has already failed all standard treatments and whose health is too compromised to qualify for participation in randomized clinical trials.
- Fixed trials consider existing data only during the trial’s design, do not modify the trial after it begins, and do not assess the results until the study is completed.
- Adaptive clinical trials are the trial that evaluates a treatment or medical device by observing participant outcomes (such as side-effects) on a prescribed schedule and modifying parameters of the trial protocol in accordance with those observations. The adaptation process generally continues throughout the trial, as prescribed in the trial protocol.
The clinical trials are divided into phases from phase 0/I to Phase IV trials. Starting from Phase I, the drug/device after the success of each phase moves to the next phase. All these phases’ data are submitted to the regulatory authority for approval.
Phases of study
|Phase 0||Pharmacodynamics and pharmacokinetics in humans||Phase 0 trials are optional first-in-human trials. Single subtherapeutic doses of the study drug or treatment are given to a small number of subjects (typically 10 to 15 subjects) to collect preliminary data on the substance pharmacodynamics and pharmacokinetics. For a test drug, the trial documents the absorption, distribution, metabolization, excretion, and the drug’s interactions within the body, to confirm that these appear to be as expected.||–|
|Phase I||Safety screening||Phase I studies are first-in-person trials. Testing within a small group of people (typically involves 20–100 subjects to evaluate the safety, determine safe dosage ranges, and identify side effects.||Several months|
|Phase II a/b||preliminary efficacy of the drug usually against a placebo control group||Phase IIa studies are specifically designed to assess dosing requirements while a Phase IIb trial is designed to determine the efficacy, and studies how well the drug works at the prescribed dose(s), establishing a therapeutic dose range.||Several months to 2 years|
|Phase III||Final confirmation of safety and efficacy||Phase III involves testing with large groups of people (typically 1,000–3,000 subjects) to confirm its efficacy, evaluate its effectiveness, monitor side effects, compare it to commonly used treatments, and collect information that will allow it to be used safely.||1 to 4 years|
|Phase IV||Safety studies during sales||Postmarketing studies delineate risks, benefits, and optimal use. As such, they are ongoing during the drug’s lifetime of active medical use.||–|
Clinical trials design
- Observational study
- In an observational study, the investigators observe the subjects and measure their outcomes. This is in contrast to randomized controlled trials where investigators do intervene and look at the effects of the intervention on an outcome.
- Interventional study
- In an interventional study, the investigators give the research subjects an experimental drug, or use of a medical device, diagnostic or other intervention to compare the treated subjects with those receiving no treatment or the standard treatment. Then the researchers assess how the subjects’ health changes.
- Active control studies
- Giving a placebo to a person suffering from a disease may be unethical. So to address this, it has become a common practice to conduct “active control” (also known as “active comparator”) trials.
- In trials with an active control group, subjects are given either the experimental treatment or a previously approved treatment with known effectiveness.
Clinical trial protocol
A clinical trial protocol is a document used to define and manage the trial. The protocol contains a precise study plan to assure the safety and health of the trial subjects and to provide an exact template for trial conduct by investigators.
- It is prepared by a panel of experts. All study investigators are expected to strictly observe the protocol.
- The protocol describes the scientific rationale, objective(s), design, methodology, statistical considerations, and organization of the planned trial.
- Details of the trial are provided in documents referenced in the protocol, such as an investigator’s brochure.
- The format and content of clinical trial protocols sponsored by pharmaceutical, biotechnology or medical device companies in the United States, European Union, or Japan have been standardized to follow Good Clinical Practice guidance which is issued by the International Conference on Harmonization of Technical Requirements for Registration of Pharmaceuticals for Human Use (ICH)
- Regulatory authorities in Canada and Australia also follow ICH guidelines.
Before initiating clinical trials
Before you start your clinical trial there are many factors to minimize unnecessary cost, delays, and/or failures. This process is known as the Drug development strategy. Let’s discuss in detail below
What is a drug development strategy?
Drug development strategy is an optimized and dynamic process that moves forward in defined stages. A carefully planned set of steps, and visionary interpretations progressing from pre-clinical to the first-in-human Phase I to Phase II “proof of concept” and pivotal Phase III trials for registration
A well-designed strategy will help you consider the following points
- Why do you need to conduct this clinical trial? What is the primary goal of the trial?
- Determining the pathway
- Are there any exceptions, accelerated processes, post-approval data submission, etc? Are there any strategies that may Fastrack the process?
- Check whether your trials are eligible for regulatory benefits and incentives
- Determine the type of clinical trial, the trial design you need to perform
- Feasibility studies
- Conducting regional feasibility (Country-level feasibility) to identify and evaluate feasible regions for conducting clinical trials
- Understand the regulatory process and ethical approvals and timelines
- Find the disease prevalence and patient population available for recruitment, recruitment and retention rate to minimize delays
- Identify the sites and qualified clinical investigators (Site-level and investigator level feasibility)
- Estimate the time and cost involved
- Evaluate the global acceptance for the clinical trial data generated under the regulatory chosen
- Compile the dossier for submission
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