Clinical Research Phases and the Path to Drug Approval

Getting a drug from the bench to the bedside takes around 10-15 years and around 6-7 of those years are spent in clinical trials. While it’s difficult to determine the exact amount, the cost of drug development appears to range from less than $1 billion to more than $2 billion USD. Here are the steps a drug takes on its path to approval with an in-depth review of the 4 clinical research phases and how they fit into the drug approval process.

Goals of Clinical Research

Clinical trials look at new ways to prevent, detect, or treat disease.

Clinical trials can study:

• New drugs or new combinations of drugs
• New ways of doing surgery
• New medical devices
• New ways to use existing treatments
• New ways to change behaviors to improve health
• New ways to improve the quality of life for people with acute or chronic illnesses

Common goals for studies with an experimental drug:

• Learn if it has the desired effect (really does what we think it does)
• Determine the most effective and safe dosage
• Discover side effects and make sure the risk of the side effects isn’t worse than the disease to be treated
• Learn how a drug is broken down in the body, and how long it stays in the body
• Determine which foods, drinks, herbals, or other drugs can be used at the same time as the experimental drug and what should be avoided because it could cause an adverse reaction

Clinical Trials

Clinical research trial results allow the FDA and regulatory agencies in other countries to decide whether a drug or device is safe and effective in people and should be approved to go to market.

The drugs and devices used in clinical trial phases 0-3 are not approved for the intended use, but the clinical trials are performed under the scrutiny of the governing regulatory agency (FDA in the U.S.) or according to their criteria.

A drug may be considered “new” even if it has been in use for years provided a change is proposed in its use, packaging, formulation, route of administration, or use in the patient population where the risk would be increased.

For example, years ago, the FDA approved a drug to treat high blood pressure. The manufacturer of the drug now wants to test it as a treatment for anxiety in adults. This new use of the drug would be considered investigational.

Path to Drug Approval

When a sponsor (drug developer) develops a new compound and wants to seek approval, there are several steps the new drug needs to go through to demonstrate it is safe and effective.

Preclinical studies are the first step. This type of research uses cell cultures or animals to determine preliminary efficacy, toxicity, pharmacokinetics (how the drug works in the body), and safety information. If the results are promising, clinical trials may begin.

Investigational New Drug (IND)

A sponsor that wishes to conduct a clinical trial involving a new drug (such as a drug, vaccine, or biological product for which FDA approval is being sought) must submit an Investigational New Drug application (IND) to the FDA. The FDA reviews the IND application for the safety of the drugs’ use in people and to assure that the proposed clinical trials don’t pose an unreasonable risk to human subjects. The FDA also verifies there is adequate Informed consent and human subject protection.

The following must be filed and reviewed by the FDA before an IND is assigned:

• Animal testing results show the drug is reasonably safe to be used in people
• Clinical protocols (study plans) for the conduct of clinical trials
• Experience with the drug in other countries and data from any prior human research
• Manufacturing information
• Dependence and abuse potential
• Information about the investigator overseeing the study

In the U.S., clinical trials can only start after the IND is reviewed by the FDA and a protocol is reviewed and approved by an Institutional Review Board (IRB).

An IRB is an independent body established to protect the rights and welfare of human research participants. IRBs make sure the study is acceptable, that participants have given consent and are fully informed of their risks, and that researchers take appropriate steps to protect patients from harm.

Outside of the U.S., studies are reviewed similarly by an IRB or ethics committee specific to their country or region.

The Path to Approval: Clinical Research Phases

New treatments go through the following phases of clinical research:

Phase O trials

First-in-human clinical trial (optional) with 10 to 15 healthy volunteers where small amounts of the investigational drug are given to check if the drug behaves as expected in humans. If the medication acts differently than expected, additional preclinical research will most likely be completed before deciding whether to continue.

Phase I trials

Researchers test a drug or treatment in 20 to 80 people (many times a first-in-human study) that are often healthy volunteers to see if the drug or treatment is safe, identify side effects, and determine safe dosage ranges. Recruiting patients for this phase often involves finding healthy volunteers willing to go through rigorous testing while staying at the research facility.

Phase II trials

The investigational drug is given to a larger group (hundreds) of people who have the disease of interest. This is to determine its effectiveness and to further study safety, short-term side effects, and dosages. Sometimes phase 2 studies are divided into phases 2a and 2b:

• 2a (proof of concept) – determine the drug’s mechanism of action and how the drug affects the body to show efficacy in people with the target disease. If efficacy isn’t shown to be promising, further testing won’t occur.
• 2b (dose-response studies) – determine the optimal dosage(s) to use for further studies.

Participants for phase II research need to have the target disease but not a lot of comorbidities. Inclusion and exclusion criteria are more restrictive, making recruitment a challenge. A targeted recruitment plan is needed.

Phase III trials

The investigational drug or treatment is given to large groups of people (thousands) to confirm its effectiveness, monitor side effects, compare it with standard or similar treatments, and collect information that will allow the new drug or treatment to be used safely. Sometimes phase 3 studies are done as 3a and 3b:

• 3a (pivotal trials) – confirm the safety and effectiveness of a larger population, and support initial claims of the sponsor to regulatory authorities. This phase is done before obtaining first indication approval (the drug has been shown to be safe and effective for its intended use).
• 3b (after 3a completed) – gather additional data, such as best use of the drug in real-world settings, patient subpopulations, long-term outcomes, or effects on quality of life. This phase begins after obtaining the first approved indication from the regulatory authority and before getting marketing approval with accurate labeling of the drug.

Phase III study Inclusion and exclusion criteria are less restrictive, but a large number of patients are needed, often from several countries. A strong global recruitment plan is needed.

Phase IV trials

After a drug is approved by the FDA and made available to the public, researchers track its safety and effectiveness in the general population (thousands of participants), seeking more information about a drug’s benefits, optimal use, and long-term effects.

New Drug Application (NDA)

The FDA has a review meeting with the drug sponsor before the submission of an NDA. The NDA is the vehicle through which drug sponsors formally propose that the FDA approve a new pharmaceutical for sale and marketing in the U.S. The data gathered during preclinical and phases 0-3 of clinical studies of an IND become part of the NDA. To obtain approval, the NDA must provide enough information to permit the FDA reviewers to determine if:

• The drug is safe and effective for its proposed use(s)
• The benefits of the drug outweigh the risks
• The drug’s proposed labeling (package insert) is appropriate
• The methods used in manufacturing the drug and the controls used to maintain the drug’s quality are adequate to preserve the drug’s identity, strength, quality, and purity

The documentation required in an NDA is supposed to tell the drug’s whole story. This includes what happened during the clinical research phases of testing, the ingredients of the drug, the results of the animal studies, how the drug behaves in the body, and how it is manufactured, processed, and packaged.

Once the NDA has been submitted, the FDA has 60 days to determine if it is complete enough for review. If the NDA is filed for review, an FDA team evaluates the safety and efficacy of the research submitted by the study sponsor. Reviewers determine whether they agree with the sponsor’s results and conclusions, or whether they need any additional information to decide. FDA inspectors also travel to clinical study sites to conduct routine inspections. They look for evidence of fabrication, manipulation, or withholding of data. The review team issues a recommendation, and a senior FDA official decides.

Drug Labeling

Once the FDA decides a drug is safe and effective in its intended use, they work with the sponsor on accurate drug labeling. Labeling includes:

• Prescribing information for health care professionals
• Carton and container labeling
• Information for patients or caregivers (e.g., Medication Guides and Patient Package Inserts)

The FDA inspects the plants where the drug is manufactured. They will either approve the NDA or send a response letter.

There are faster ways for approvals to occur for drugs that treat serious or life-threatening diseases or fulfill an unmet need. More information is available at https://www.fda.gov/drugs/development-approval-process-drugs. For example, drugs treating rare diseases or life-threatening diagnoses.

Phase IV Clinical Trials

After a drug is approved by the FDA and made available to the public, researchers track its safety and effectiveness in the general population. This is done through Phase IV clinical trials. The intention of these trials is to:

• Seek more information about the drug’s benefits
• Optimal use
• Rarer side effects
• Long-term effects

Information gathered from Phase IV studies could cause a change in labeling. Such as updating side effects, or use in combination with other illnesses/medications. Also, removal from the market could occur if too much risk is detected.

The Imperial Advantage in All Clinical Research Phases

Each clinical research phase requires unique strategies for recruiting and enrolling patients. Imperial Clinical Research Services has vast experience developing, translating, and printing recruitment materials for all clinical research phases for use in global studies. Additionally, Imperial keeps your study on track to avoid delays.

Dan McDonald’s blog on study startup and execution discusses why “Getting that first patient into the study on time is critical. If that goal isn’t met, it takes longer to gain traction and raises the likelihood that you will not hit your clinical trial enrollment targets. Your study will not meet its timelines.”

We also help with local requirements. Most phase 3 trials are international. Differences in local requirements from country to country make multinational studies especially challenging. Customization is required to conduct the study at a local level. This includes maintenance, calibration, disposition, customs clearance and import regulations, technology infrastructure, regulated devices, instructions for use, and translations.

Erica Manning reminds us in her clinical trial translation blog that “Accurate clinical trial translation services are key to the overall success of a study. Each participant needs to receive the same information in their native language to ensure consistent study messaging across all languages and accuracy to the protocol.”

Imperial translation services’ quality management system is certified to ISO 9001:2015 by Intertek. This demonstrates a commitment to quality for your clinical trial translations.

Contact us for more information on how we can save time and money for your clinical trials.