Have you ever wondered about the long and arduous journey that a drug goes through before coming to pharmacy stores?

Overview

The journey begins in a laboratory where researchers, spending hours and hours to understand the processes behind a disease and stumble upon a potential target. This target can be a gene or a protein instrumental in the progression of the disease at a cellular or molecular level.It is through blocking this target that the disease could be stopped or so it is presumed.

The first step, structural predictions, is performed in silico with help of computer algorithms and simulators. The predicted molecules are somewhat modified from other drugs, cellular molecules or natural compounds. With current advancements in technology, thousands of molecules can be screened by high-throughput screening and the most suited results are the so-called “lead compounds”.

These substances have an expected biological or pharmacological activity, but they are far from being the final drug. They are more likely a prototype, which can be modified in order to be more functional or less toxic. During in silico analysis, more than 10,000 compounds are identified and their chemical, physical and biological properties are thoroughly examined.

Only about 20 compounds will be chosen as leading compounds and they can toward it to the next step.

In ‘preclinical trials’, substances are tested not only in vitro, on cell cultures or on artificial systems which mimic biological environments, but also in vivo, on model animals.

The first hints about toxicity, strength, and doses are registered. But they are better determined with in vivo tests on animals. These latter experiments elucidate the drug metabolism much better.  At the end of the preclinical trial, only a few leading compounds have the right property to reach the last phase, the ‘clinical trials.’

The last, but the most essential part of the drug testing is the most expensive and time-consuming. There arethree phases before the final approval and a fourth one, which is when the drug is officially ratified.

Phase I clinical trial involves only a few tens of healthy volunteers and it mainly evaluates the drug tolerance.

The kinetics of the compounds and their possible side effects are monitored. During this step, many drugs are excluded from the study due to bad kinetics.

Thereafter, phase II trials include a bigger cohort: 100-300 people affected by the disease. After informed consent, patients are treated with different doses of the new drug or with a placebo (a compound that has no biological nor pharmaceutical activity in respect to the target under examination). Basically, a dummy drug.

Further, to avoid psychological influences, doctor implement a so-called “blind study”. The doctor knows which therapy is given to the patient, but the patients do not. Whereas, in a “double blind study”, neither the doctor nor the patient knows which treatment is administered. However, an external group of scientists monitors these types of studies.

A more robust phase III clinical trial remains. Groups of scientists and doctors monitor a broader number of patient (up to 3000) in this phase. These patients comprise of different hospitals and, for a better study, even from different nations.

The goal of the analysis is to confirm the efficacy and the safety of the drug, to monitor the long-term side effects and to improve the doses and the way of administration.

If all goes according to plan, the drug then goes for approval by the national medicine agency, for Europe it is the European Medicines Agency (EMA) and for the United states it is the Federal Drug Administration (FDA). The authorities check the data thoroughly and decide if the new drug can be produced and sold.

However, the controls do not end here! The scientists can decide to start a phase IV clinical trial, which involves a bigger number of patients to assess further safety concerns, efficacy and long-term side effects.

Moreover, there is an external national committee, which registers every side effect and monitors constantly the efficacy of the medicine. The process, called as pharmacovigilance lasts as long as the drug is sold and used.

Each year, there are only a couple of dozen new drugs licensed for use. But in their wake, there are hundreds of thousands of candidate drugs that fail to clear these hurdles.

On an average, the research and development journey of these new drugs that make it to market takes between 6-12 years and cost up to $1b.

 

The Drug Development Paradigm

Step 1: Discovery and Development

Discovery

Typically, researchers discover new drugs through:

• New insights into a disease process that allow researchers to design a product to stop or reverse the effects of the disease.
• Many tests of molecular compounds to find possible beneficial effects against any of a large number of diseases.
• Existing treatments that have unanticipated effects.
• New technologies, such as those that provide new ways to target medical products to specific sites within the body or to manipulate genetic material.

At this stage in the process, thousands of compounds may bepotential candidates for development as a medical treatment. After early testing, however, only a small number of compounds look promising and call for further study.

Development

Once researchers identify a promising compound for development, they conduct experiments to gather information on:

• How it is absorbed, distributed, metabolized, and excreted.
• Its potential benefits and mechanisms of action.
• The best dosage.
• The best way to give the drug (such as by mouth or injection).
• Side effects or adverse events that can often be referred to as toxicity.
• How it affects different groups of people (such as by gender, race, or ethnicity) differently.
• How it interacts with other drugs and treatments.
• Its effectiveness as compared with similar drugs

 

Step 2: Preclinical Research

Before testing a drug in people, researchers must find out whether it has the potential to cause serious harm, also called toxicity. The two types of preclinical research are:

• In Vitro
• In Vivo

FDA requires researchers to use good laboratory practices (GLP), defined in medical product development regulations, for preclinical laboratory studies.  The GLP regulations are found in 21 CFR Part 58.1: Good Laboratory Practice for Nonclinical Laboratory Studies. These regulations set the minimum basic requirements for:

• study conduct
• personnel
• facilities
• equipment
• 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

Usually, preclinical studies are not very large. 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.\

 

Step 3: Clinical Research

While preclinical research answers basic questions about a drug’s safety, it is not a substitute for studies of ways the drug will interact with the human body. “Clinical research” refers to studies, or trials, that are done in people. As the developers design the clinical study, they will consider what they want to accomplish for each of the different Clinical Research Phases and begin the Investigational New Drug Process (IND), a process they must go through before clinical research begins.

 

Step 4: FDA Drug Review

A drug developer has evidence from its early tests and preclinical and clinical research that a drug is safe and effective for its intended use, the company can file an application to market the drug. The FDA review team thoroughly examines all submitted data on the drug and makes a decision to approve or not to approve it.

 

Step 5: FDA Post-Market Drug Safety Monitoring

Even though clinical trials provide important information on a drug’s efficacy and safety, it is impossible to have complete information about the safety of a drug at the time of approval. Despite the rigorous steps in the process of drug development, limitations exist. Therefore, the true picture of a product’s safety actually evolves over the months and even years that make up a product’s lifetime in the marketplace. FDA reviews reports of problems with prescription and over-the-counter drugs, and can decide to add cautions to the dosage or usage information, as well as other measures for more serious issues.

 

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

 

Clinical Research Studies

Clinical trials follow a typical series from early, small-scale, Phase 1 studies to late-stage, large scale, Phase 3 studies.

 

Phase 1

Study Participants: 20 to 100 healthy volunteers or people with the disease/condition.

Length of Study: Several months

Purpose: Safety and dosage

Approximately 70% of drugs move to the next phase

 

Phase 2

Study Participants: Up to several hundred people with the disease/condition.

Length of Study: Several months to 2 years

Purpose: Efficacy and side effects

Approximately 33% of drugs move to the next phase

 

Phase 3

Study Participants: 300 to 3,000 volunteers who have the disease or condition

Length of Study: 1 to 4 years

Purpose: Efficacy and monitoring of adverse reactions

Approximately 25-30% of drugs move to the next phase

 

Phase 4

Study Participants: Several thousand volunteers who have the disease/condition

Purpose: Safety and efficacy

 

The Investigational New Drug Process

Drug developers, or sponsors, must submit an Investigational New Drug (IND) application to FDA before beginning clinical research.

In the IND application, developers must include:

• Animal study data and toxicity (side effects that cause great harm) data
• Manufacturing information
• Clinical protocols (study plans) for studies to be conducted
• Data from any prior human research
• Information about the investigator

 

Asking for FDA Assistance

Drug developers are free to ask for help from FDA at any point in the drug development process, including:

• Pre-IND application, to review FDA guidance documents and get answers to questions that may help enhance their research
• After Phase 2, to obtain guidance on the design of large Phase 3 studies
• Any time during the process, to obtain an assessment of the IND application

Even though FDA offers extensive technical assistance, drug developers are not required to take FDA’s suggestions. As long as clinical trials are thoughtfully designed, reflect what developers know about a product, safeguard participants, and otherwise meet Federal standards, FDA allows wide latitude in clinical trial design.

 

FDA IND Review Team

The review team consists of a group of specialists in different scientific fields. Each member has different responsibilities.

• Project Manager: Coordinates the team’s activities throughout the review process, and is the primary contact for the sponsor.
• Medical Officer: Reviews all clinical study information and data before, during, and after the trial is complete.
• Statistician: Interprets clinical trial designs and data, and works closely with the medical officer to evaluate protocols and safety and efficacy data.
• Pharmacologist: Reviews preclinical studies.
• Pharmakineticist: Focuses on the drug’s absorption, distribution, metabolism, and excretion processes.Interprets blood-level data at different time intervals from clinical trials, as a way to assess drug dosages and administration schedules.
• Chemist: Evaluates a drug’s chemical compounds. Analyzes how a drug was made and its stability, quality control, continuity, the presence of impurities, etc.
• Microbiologist: Reviews the data submitted, if the product is an antimicrobial product, to assess response across different classes of microbes.

 

IND Approval

The FDA review team has 30 days to review the original IND submission. The process protects volunteers who participate in clinical trials from unreasonable and significant risk in clinical trials. FDA responds to IND applications in one of two ways:

• Approval to begin clinical trials.
• Clinical hold to delay or stop the investigation. FDA can place a clinical hold for specific reasons, including:
  • Participants are exposed to unreasonable or significant risk.
  • Investigators are not qualified.
  • Materials for the volunteer participants are misleading.
  • The IND application does not include enough information about the trial’s risks.

A clinical hold is rare; instead, FDA often provides comments intended to improve the quality of a clinical trial. In most cases, if FDA is satisfied that the trial meets Federal standards, the applicant is allowed to proceed with the proposed study.

The developer is responsible for informing the review team about new protocols, as well as serious side effects seen during the trial. This information ensures that the team can monitor the trials carefully for signs of any problems. After the trial ends, researchers must submit study reports.

This process continues until the developer decides to end clinical trials or files a marketing application. Before filing a marketing application, a developer must have adequate data from two large, controlled clinical trials

 

New Drug Application

 

A New Drug Application (NDA) tells the full story of a drug. Its purpose is to demonstrate that a drug is safe and effective for its intended use in the population studied.

A drug developer must include everything about a drug—from preclinical data to Phase 3 trial data—in an NDA. Developers must include reports on all studies, data, and analyses. Along with clinical results, developers must include:

• Proposed labeling
• Safety updates
• Drug abuse information
• Patent information
• Any data from studies that may have been conducted outside the United States
• Institutional review board compliance information
• Directions for use

 

FDA NDA Review

Once FDA receives an NDA, the review team decides if it is complete. If it is not complete, the review team can refuse to file the NDA. If it is complete, the review team has 6 to 10 months to make a decision on whether to approve the drug. The process includes the following:

• Each member of the review team conducts a full review of his or her section of the application. For example, the medical officer and the statistician review clinical data, while a pharmacologist reviews the data from animal studies. Within each technical discipline represented on the team, there is also a supervisory review.
• FDA inspectors travel to clinical study sites to conduct a routine inspection. The Agency looks for evidence of fabrication, manipulation, or withholding of data.
• The project manager assembles all individual reviews and other documents, such as the inspection report, into an “action package.” This document becomes the record for FDA review. The review team issues a recommendation, and a senior FDA official makes a decision.

 

FDA Advisory Committees

Often, the NDA contains sufficient data for FDA to determine the safety and effectiveness of a drug. Sometimes, though, questions arise that require additional consideration. In these cases, FDA may organize a meeting of one of its Advisory Committees to get independent, expert advice and to permit the public to make comments. These Advisory Committees include a Patient Representative that provides input from the patient perspective. Learn more about FDA Advisory Committees.

 

FDA Approval

In cases where FDA determines that a drug has been shown to be safe and effective for its intended use, it is then necessary to work with the applicant to develop and refine prescribing information. This is referred to as “labeling.” Labeling accurately and objectively describes the basis for approval and how best to use the drug.

Often, though, remaining issues need to be resolved before the drug can be approved for marketing. Sometimes FDA requires the developer to address questions based on existing data. In other cases, FDA requires additional studies. At this point, the developer can decide whether or not to continue further development. If a developer disagrees with an FDA decision, there are mechanisms for formal appeal.

 

Supplemental Applications

 

Developers must file a supplemental application if they wish to make any significant changes from the original NDA. Generally, any changes in formulation, labeling, or dosage strength must be approved by FDA before they can be made.

 

INDs for Marketed Drugs

 

If sponsors want to further develop an approved drug for a new use, dosage strength, new form, or different form (such as an injectable or oral liquid, as opposed to tablet form), or if they want to conduct other clinical research or a post-market safety study, they would do so under an IND.

 

Manufacturer Inspections

 

FDA officials conduct routine inspections of drug manufacturing facilities across the United States, and abroad if approved products are manufactured overseas. Manufacturers may be informed of inspections in advance, or the inspections may be unannounced. Inspections may be routine or caused by a particular problem or concern. The purpose of these inspections is to make sure that developers are following good manufacturer practice. FDA can shut down a facility if minimum standards are not met.

 

Drug Advertising

 

FDA regulates prescription drug advertisements and promotional labeling. By law, a developer is prohibited from advertising unapproved uses of their product.

All advertisements, such as product claims or reminder ads, cannot be false or misleading. They must contain truthful information about a drug’s effectiveness, side effects, and prescribing information. These advertisements can be found in medical journals, newspapers, and magazines, and on the Internet, television, or radio.

Promotional labeling differs from drug advertisements in the way it is distributed. Pharmaceutical companies give out brochures or other promotional materials to physicians or consumers. The drug’s prescribing information must accompany promotional labeling.

 

Generic Drugs

 

New drugs are patent protected when they are approved for marketing. This means that only the sponsor has the right to market the drug exclusively. Once the patent expires, other drug manufacturers can develop the drug, which will be known as a generic version of the drug. Generic drugs are comparable to brand name drugs and must have the same:

• Dosage form
• Strength
• Safety
• Quality
• Performance characteristics
• Intended use

Because generic drugs are comparable to drugs already on the market, generic drug manufacturers do not have to conduct clinical trials to demonstrate that their product is safe and effective. Instead, they conduct bio-equivalence studies and file an Abbreviated New Drug Application.

Reporting Problems

FDA has several programs that allow manufacturers, health professionals, and consumers to report problems associated with approved drugs.

• MedWatch is a gateway for reporting problems with medical products (drugs and devices) and learning about new safety information. You can subscribe to regular MedWatch safety alerts.
• Medical Product Safety Network (MedSun) monitors the safety and effectiveness of medical devices. FDA recruits 350 healthcare providers throughout the United States to report any medical device problems that result in serious injury or death. Each month, FDA publishes the MedSun newsletter. The newsletter gives consumers important information about medical device safety.

 

Active Surveillance

 

Under the Sentinel Initiative, FDA is developing a new national system to more quickly spot possible safety issues. The system will use very large existing electronic health databases—like electronic health records systems, administrative and insurance claims databases, and registries—to keep an eye on the safety of approved medical products in real time. This tool adds to, not replace, FDA’s existing postmarket safety assessment tools

 

In Summary….

Drug development is complex paradigm that at times may seem overwhelming. Feel free to contact RhoTau Pharma Services LLC for additional information or assistance with your drug development questions or issues. We have the expertise to help you navigate through your challenges and meet you goal of a timely and successful drug development.