Explainer: The Clinical Development Path

The ultimate goal of clinical development is to obtain the clinical information that will be included on the labelling of the new medicine. This will inform both healthcare professionals and patients about how to use the new drug correctly and safely.

Clinical trial results must also satisfy regulatory authorities, e.g., US Food and Drug Administration (FDA), European Medicines Agency (EMA), Pharmaceuticals and Medical Devices Agency (PMDA, Japan), and others to secure approval of the new therapy, as well as governmental bodies responsible for reimbursement and patient care organisations, so that the drug can be marketed and made available to patients.

A Multi-Phase Process

Irrespective of the type of drug or disease in focus, we can look at clinical development as a generalised path that takes place over multiple phases. If clinical development is successful, the result is a new approved therapy.

Clinical development was traditionally much more step-wise than it is nowadays, with very clearly defined and distinct phases. Today, the margins between these phases are becoming less distinct as drug development programmes become more seamless.

IND (Investigational New Drug) Filing

Although not strictly a part of clinical development, IND filing is a requisite before beginning any clinical trial in the US. Here, the sponsor, which is usually the company developing the new drug, must submit an Investigational New Drug application to the FDA detailing the preliminary data on the drug gathered from cellular models and animal studies. Toxicology safety evaluations can be based on draft reports as long as the data is sufficient for the FDA to make a reasonable assessment about safety of the new drug before clinical development ensues.

According to the FDA: 'FDA's role in the development of a new drug begins when the drug's sponsor (usually the manufacturer or potential marketer), having screened the new molecule for pharmacological activity and acute toxicity potential in animals, wants to test its diagnostic or therapeutic potential in humans. At that point, the molecule changes in legal status under the Federal Food, Drug, and Cosmetic Act and becomes a new drug subject to specific requirements of the drug regulatory system.'

In Europe, preliminary safety data is included with a clinical trial application (CTA).

Once approval is obtained for clinical testing by the relevant regulatory body, the programme may enter clinical development in that territory.

Phase I

Often called ‘first-in-man’, Phase I is probably more accurately described as a clinical pharmacology phase. It is indeed during Phase I that the IND is administered to human beings for the first time, but in practice, a typical Phase I may contain many (10 - 20) different studies, that together provide extensive information about clinical pharmacology of the new drug.

The overall goals of Phase I include:

• Dose finding. This usually involves a single ascending dose study (Phase Ia) followed by a multiple ascending dose study (Phase Ib). In Phase Ia (also called first dose in man), 3-5 volunteers are given a one-off single dose and observed by medical staff for a period of time. If they do not exhibit adverse side effects, and the pharmacokinetic data is roughly in line with predicted safe values, a new group of volunteers will be given a higher one-off dose. If the first group exhibits adverse side effects, the new group will receive the same dose. This process is iterated until theoretical pharmacokinetic safety levels are reached, or intolerable side effects appear, at which point the drug is said to have reached the maximum tolerated dose (MTD). Calculating the MTD is important to establish a therapeutic window i.e. the dose range in which the new drug is effective as well as safe and well tolerated. A Phase 1a study also examines the affect of taking the drug with or without food (if orally administered). Phase Ib examines the pharmacokinetics and pharmacodynamics of multiple doses of the drug, including safety and tolerability. Here, volunteers receive multiple low doses of the drug, while biological samples (e.g., blood) are collected at various time points and analysed to determine how the drug is processed within the body. The dose is subsequently escalated for further groups, up to a predetermined level.
• Pharmacokinetics and pharmacodynamics studies. The pharmacokinetics, metabolism and safety of the intended new drug are assessed both when given alone and in combination with other drugs that have the potential to interact with the new drug. How the drug moves around the body, how long it takes to get to the blood and organs, how long it stays in the body, how it is cleared from the body and whether it yields toxic metabolites are some of the pharmacokinetic parameters studied here. Understanding the pharmacodynamics i.e. how the body responds to various doses of the drug is also important to help select the dose in later phases. This may include the use of measurable biological or surrogate markers when available, e.g., a readout of stomach acid secretion during Phase I for a new antacid.
• To ascertain how the drug is handled by certain populations, e.g., elderly, particular ethnicities, and those with kidney or liver impairments.
• Safety. Besides safe dose finding, Phase I also includes special safety tests including QT studies. Here, new drugs are assessed for their ability to cause QT prolongation, a potentially fatal side effect whereby the heart muscle takes longer than normal to recharge between beats. QT testing has become a general requirement for all new drugs in recent years. Other safety tests may include effects on driving ability and risk for drug abuse, especially for drugs that target the brain.

Phase I studies are performed by medical staff in specialised hospital units or in dedicated centers close to hospitals. The studies are usually double-blind and placebo-controlled. The doses used in these studies are guided by pre-clinical toxicology studies. Testing units are equipped for administration of the new drug, which depending on its nature may be given intravenously, inhaled, in tablet form, subcutaneously or otherwise. These units also have the setup to collect and store relevant clinical samples for analysis, e.g., blood or urine samples. They also manage patient safety and must be ready to perform resuscitation or other interventions in the event of significant side effects.

The subjects involved in Phase I are usually healthy volunteers that are often selected from volunteer databases held at the specialised units. Phase Ia studies are often conducted in male subjects between 18-45 years of age. The idea is to have as homogeneous a population as possible, and males are often preferred for reproductive safety reasons. In this very early stage of clinical development, animal toxicity studies might not yet be completed, and so the risk of harm to foetuses of pregnant subjects or the risk of toxic effects in a pregnancy that might occur soon after the study cannot be excluded.

In exceptional cases, a Phase I study may include patients of severe (e.g., genetic) diseases for which there are no approved therapies at all, or very ill patients who have not responded to existing therapies. This is also seen within the CRISPR medicine field in particular for the treatment of advanced cancers, e.g., the first CRISPR trial and the first Chinese CRISPR trial that were conducted to test the safety and feasibility of CRISPR-based therapies. Both of these Phase I studies enrolled severely ill patients who were injected with CRISPR-Cas9 edited T cells that were engineered to make the cancer cells more visible to the immune system.

Phase IIa - Exploratory Efficacy - Does The New Drug Work?

The scope of Phase IIa will depend on whether the new drug has a completely novel mechanism of action or whether it is an improvement to already-marketed drugs i.e. an add-on drug. In the case of completely novel drugs, Phase IIa will be the new drug's first efficacy test and will serve as a Proof of Concept (PoC), revealing how well results from animal disease models translate to human patients.

PoC studies are critical for making a go/no-go decision about a new drug during clinical development. Therefore, Phase IIa design is critical; it must be able to reveal whether clinical efficacy is present or not to inform downstream steps. For add-on drugs, Phase IIa is used to identify differentiators i.e. how does the new drug differ from marketed drugs with the same mechanism of action. This may include factors such as side effects, speed and duration of action.

Since Phase II studies are small in size and lack the statistical power to reveal significant treatment benefits, they must be designed very carefully with explicit criteria for success or failure. How large and small pharmaceutical companies approach Phase II often differs. Large companies may proceed to Phase II to show efficacy and safety for a new compound even if certain features are less than satisfactory at this point, e.g., poor drug solubility. Once Phase II has revealed PoC, the company can then optimise the drug knowing that it has secured Phase II PoC for the novel mechanism of action. Smaller companies with less capital are more likely to enter Phase IIa with a carefully optimised new drug that it can advance directly to further development if Phase II is successful.

Phase IIa studies are often double-blinded and placebo-controlled, allowing objective safety and efficacy measurements. However, exceptions are made for ethical reasons, e.g., in oncology where the new drug is either used as an add-on to the standard therapy for a given cancer or the new drug is compared to the standard therapy. The dosing for Phase IIa is informed by Phase I findings and pre-clinical studies. The ultimate goal is to use a dose that has the best chance of revealing PoC. One or two dose groups are usually used and the MTD is often tested. The drug given in Phase IIa is rarely in its final form i.e. the final tablet or injectable because the results of Phase I and II may influence the final formulation.

The subjects included in Phase IIa are patients of the disease in question. Generally, a small homogeneous patient group is studied to avoid the risk of diluting a clinical benefit by using a large diverse group. Since the prospensity for drug-drug interactions and the side effect profile won’t be completed defined at this point, Phase IIa often includes a subgroup of patients that are considered most likely to experience a therapeutic benefit. Inclusion and exclusion criteria for subjects partaking in these studies may be restrictive. The studies are typically short and the outcome measures need to be very robust. One main objective is preferred over a list of objectives, and the objectives will depend on the drug and disease. Surrogate markers may be useful to evaluate pharmacological effect when long-term treatment is needed to assess the therapeutic benefit of a new drug, e.g., measurements of inflammatory mediators for a new drug developed for inflammatory bowel disease. Pharmacokinetic studies can also be undertaken during Phase IIa to see whether the drug behaves differently in healthy volunteers vs. patients, e.g., whether the disease itself affects the absorption of the drug in the body. Such studies can help to inform dosing for Phase IIb.

Phase IIb/Phase III - Is the New Drug Better Than What's Already out There?

The goal here is to confirm the efficacy seen in Phase IIa PoC studies and to ultimately generate the data that will support the new drug application (NDA) for market authorisation from the relevant regulatory bodies. These studies need to be large enough to carry statistical power and therefore include larger numbers. The results should provide the labelling information necessary to market the new drug, and to realise this, the clinical developers must maintain close contact with regulatory and marketing experts to ensure that trials are designed smartly.

Phase IIb is a dose-finding phase whereby the preliminary safety and efficacy data is confirmed and the dose-response relationship of the drug is further investigated over a larger number of individuals than in Phase IIa. This data is then used to select the dose with optimal efficacy and safety for the large-scale Phase III study, often referred to as a pivotal trial. The results of this Phase III study will eventually serve as evidence for market authorisation approval by regulatory bodies.

Phase IIb studies are double-blind placebo-controlled (or active comparator controlled i.e. a known, effective treatment) where one group is given the new drug (or new drug plus standard treatment/comparator) and another group is given a placebo or a comparator alone. Even though a placebo should not have any therapeutic effect on the disease, it is well documented that patients do respond to placebos during clinical trials and a number of strategies are available to minimise the impact of this so-called placebo effect. Whether placebos or active comparator is used depends on the disease in question i.e. there may be no other drug available, as well as geographical differences as imposed by regulatory bodies. Statistical analyes are carried out before the trial begins to ensure that the sample size can demonstrate statistically robust efficacy and safety data.

Phase IIb/III studies take place in a real-life setting. This is important given that these studies dictate whether the new drug is approved for use in the patient population. Inclusion and exclusion criteria are less restrictive than in Phase IIa since it is now important to represent the patient population broadly. Diverse countries, sites and doctors will be involved in a Phase IIb/III study although it is not essential to have a study site in every country the drug is intended to be marketed in. In cases where ethnicity may impact the efficacy or safety of a new drug, bridging studies may be necessary to examine these effects in more detail before a drug can be marketed in certain populations.

The outcome measure must demonstrate clinically meaningful benefit of the new drug. The surrogate efficacy measures used in Phase IIb, e.g., blood pressure reduction for cardiovascular patients is not sufficient here. Phase IIb/III must demonstrate that the new drug increases survival, life expectancy, or contributes to a significant improvement in life quality in the patient population for which it is intended. When the new drug is compared to active comparators, the outcome measures used for the already approved drugs may be used to measure the effect of the new drug. Alternative outcome measures may be used in the case of drugs with a novel mechanism of action but not without thorough negotiation with regulatory bodies.

Phase IIIb/IV

Phases I to IIIa yield a comprehensive data package that serves as the evidence required for marketing approval. However, it is still not possible at this point to conclude that all potential side effects that may emerge when the drug is marketed have been revealed. Furthermore, Phase IIIa pivotal studies may not reveal sufficient data about long-term safety of the new drug. During Phase IIIb, additional clinical trials may be undertaken to support long-term safety while marketing approval is pending. During this period or shortly after launching the new drug, companies may also wish to run new pivotal studies for additional indications.

Although Phase IIIb studies involve reasonably large patient numbers (500 - 1,000), they are not large enough to reveal rare side effects affecting fewer than 1 in 10,000 people. To capture such effects, it would be necessary to collect data from several tens of thousands of people. Generally, regulatory bodies acknowledge that this task would very time-consuming, expensive and potentially unnecessary, so they tend not to demand this before market approval. However, the work is not done once the drug is marketed. Then, Phase IV ensues where companies carry out post-market surveillance or pharmacovigilence to monitor the safety of the approved drug once it is out in the intended market. This involves collection of data about minor and major adverse events in all countries where the drug is marketed, and typically involves doctors, patients, journal articles, conference proceedings and other relevant sources.

CRISPR Clinical Trials

The CRISPR medicine field is moving fast, and there are already many clinical trials underway in broad disease areas including cancer, inherited blood disorders, metabolic disorders and viral diseases. These trials are at Phase I and II and safety data has been very promising so far. You can keep up to date with clinical trials in the CRISPR and gene editing fields with our routinely updated clinical trials register.