2015-05-20T07:19:52+00:00May 20th, 2015|


1.   Background

After new investigational drug pre-clinical stage 1 was completed, and IND (Investigational New Drug application) or CAT (Clinical Trial Application) submission to the FDA or CE (respectively) and approval, the sponsor should move forward to the clinical trial stage.

The sponsor should work on an “investigator brochure” for organizing the information about possible drug effects to the Institutional Review Board (IRB) and clinicians that will escort the clinical trial. For more information about IND and CMC requirements, refer to the ‘New drug development and regulation from pre-clinical to clinical trials article.’

For every clinical investigator, FDA form No. 1572 should be submitted. Moreover, informed consent (as defined in 21CFR part 50), IRB review, approval and reporting (as defined in 21CFR part 56) will be required.

The clinical study must be followed based on the relevant, current, approved protocol version only. Changes in protocol must be controlled, reviewed and approved by the sponsor. Records should follow Good Documentation Practices (GDP) and managed in a controlled manner and comply with 21CFR part 312 requirements.

2.   Drug development process

2.1  New Pharmaceutical, Biological Drug or Combination Medical Device product development is a prolonged process that may take 2-15 years and reach 1 billion USD in costs. For more information refer to ‘New drug development and regulation from pre-clinical to clinical trials article.’

2.2  New drug development always represents new adverse events and there will always be a risk. The FDA review team will determine whether benefits for target population using this drug outweigh the risks.

2.3  New drug development steps:

  • Drug/compound discovery
  • Pre-clinical investigations
  • IND (Investigational New Drug)
  • Clinical trials
  • NDA (New Drug Application)
  • NDA review
  • Drug product marketing

 3.   Clinical trials phases

3.1  Phase 1

Phase 1 of the drug development process is the first time the investigational drug product is being tested in humans and will include 20-80 healthy volunteers (or severely ill patients). Study duration is 6-12 months, and this study will assess investigational drug product safety, toxicity, side effects, ADME, pharmacokinetics (drug absorption, distribution, metabolism and extraction) using the chosen route of administration and “drug to drug” interactions. Phase 1 will include single and multi-dosage studies and will enable the option to assess investigational drug product safety profile through a maximal dosage range.

Phase 1 of the study will be “open label” that will not include any single/double blind methodology and will be taken usually in single center.

Phase 1 should be performed according to GCP (Good Clinical Practice) and GMP (Good Manufacturing Practice) standards, as the investigational drug product is being tested on humans. Quality Assurance, documentation, validation and other GxP standards and requirements should be followed.

3.2  Phase 2

3.2.1  General

Phase 2 of the drug development process will follow a successful phase 1 completion. The investigational drug product will be tested in humans and will include 50-300 target disease ill patients. Study duration is 1-2 years. Study will assess the investigational drug product short term side effects, risks (safety) and efficacy (dose response). In addition, phase 2 studies will test the chosen drug dosage based on dosage range investigated and determined in phase 1. At the end of phase 2, the sponsor will know whether the investigational drug product works on patients and if so, meeting with the FDA can be scheduled.

As at phase 2, investigational drug products are being tested for effectiveness on target disease patients, these patients may benefit from participating in the clinical trial.

Phase 2 study will be a double blind study, using positive control and/or placebo and will also be a multi center study. Investigational drug product that will be used by patients will be compared with similar patients receiving placebo or other commercial drug products with the same pharmacological indication. At phase 2, investigational drug product short term safety and side effects are being monitored and evaluated. Phase 2 should be performed according to the GCP (Good Clinical Practice) and GMP (Good Manufacturing Practice) as the investigational drug product is being tested on humans. Quality Assurance, documentation, Validation and other GxP standards should be followed.  As in phase 2, hundreds of patients will participate, a scale up of the pharmaceutical manufacturing GMP process usually will be required in addition to the process engineering stage that will follow GEP (Good Engineering Practice) and sanitary design considerations. In some cases, a new manufacturing technology should be considered at this stage. As phase 2 study is multi-sites, supply chain, storage transportation and Shipment Validation will be required.

3.2.2   Phase 2A and Phase 2B

There are two phase 2 trials:

Phase 2A- Continuation of phase 1, and will be performed on healthy volunteers. Phase 2A is proof of concept feasibility study.

Phase 2B- Controlled study that will be performed on target disease patients

After phase 2 completion, the sponsor should meet the FDA towards the investigational drug product pivotal trials in order to assess how the large scale studies of phase 3 should be performed.

3.3  Phase 3

3.3.1  General

Phase 3 in a drug development process will follow phase 2’s success, after the investigational drug product’s significant effectiveness was proved. Phase 3’s purpose is to provide statistically significant evidence for the investigational drug product effectiveness and safety.

In phase 3, the investigational drug product is being tested in humans and will include hundreds or thousands of target disease ill patients. Phase 3 study estimated duration is 2-3 years. Study will assess the investigational drug product safety and efficacy.

The study will test the investigational drug formulation and the basic information for labeling and package inserts for physicians and patients.  Phase 3 will include 2-4 pivotal studies in order to prove safety and efficacy of primary endpoints.

Phase 3 study will be double blind study, using positive control and/or placebo and will be a multi center study, comparing the new drug product against other similar indication commercial drug products. Phase 3 study population will be similar to the future (commercial) drug target patient population and will demonstrate that the potential benefits are higher than the risks and will optimize drug dosages and schedules based on additional data that will be analyzed during the study. Relevant information will be written on the new biological/pharmaceutical product package insert.

In comparison to phase 2, in phase 3 the new drug product will be given for a longer time period.

Phase 3 includes adequate and well controlled studies of drug/biologic such as:

  • Different doses and dosing regimens
  • Performed in different stages of the disease
  • Performed on various populations
  • Terminating on different endpoints

Phase 3 should be performed according to the GCP (Good Clinical Practice) and GMP (Good Manufacturing Practice) as the new drug product is being tested on humans. Quality Assurance, Good Documentation Practice, Validation and other GxP standards and requirements should be strictly followed.  As in phase 3, thousands of patients participate, another scale up of the pharmaceutical manufacturing process may be required and process engineering stage that will include GEP (Good Engineering Practice) and sanitary design aspects, as the study is multi-sites. Supply chain, storage transportation and Shipping Validations are mandatory.

Phase 3 will collect primary data to support marketing approval in the NDA (New Drug Application).

3.3.2  Phase 3A and Phase 3B

There are two types of phase 3 studies- Phase 3A and Phase 3B.

In phase 3B (sometimes knows as phase 4) which is post NDA submission, additional indications of the new drug product will be investigated and tested. Sometimes, product label information will be changed or updated per FDA demand, as more information on the drug product’s efficacy and side effects will be accumulated and become available. Phase 3B can be post drug approval or as condition for drug approval. Phase 3B may include studies such as compared vs. competition, post marketing surveillance, special population, rate event incidences, long terms usage data, quality of life etc.

4.   Clinical trials and clinical investigations

Informed consent should be submitted according to 21CFR part 50 to assure volunteers’ participation is truly voluntary and to verify proper disclosure of risks, potential benefits and other alternatives.

The IRB (Institutional Review Board) will review and monitor the study in order to protect humans participating in the clinical trial.

Clinical investigation should follow FDA 21CFR part 312.32 and 21CFR part 12 sub-part B which details how sponsor should report adverse effects/events and how control, distribution and return of investigational drug products is being performed and to assure sponsor investigation, protocol and practices documentation and implementation.

After the clinical trial is competed, results will be collected and analyzed. Afterwards, the sponsor will submit all relevant data to the center, a New Drug Application (NDA) or Biologics License Application (BLA), including the whole history of the investigational drug product studies and results for review. Data will include all relevant data from animal studies, human studies manufacturing and labeling data.

Within 60 days, the FDA should respond to the sponsor, notifying whether the NDA will be reviewed. The FDA will then determine whether the drug will be approved.

For accelerated approval drugs, as detailed in the next section, FDA review will take up to 6 months.

The application’s final destination at CDER will be determined based on the therapeutic indication of the new drug product and will be directed to the relevant drug product division in CDER (ODEs I, II, III, IV, V, VII).

Before CDER will apply their scientific technical expertise to review the application, they will decide about the application type review that will determine the review process duration:

Standard review– For drugs that appears to have therapeutic qualities similar to those already marketed.

Priority review– For drugs that appear to have an advantage over available therapy, if any.

5.   Investigational drug accelerated approval

In cases of new drugs for life treating and/or in cases where no satisfactory treatment exists, drugs will be considered as having “exceptional promise” and therefore will receive accelerated approval or early access programs from CDER or CBER.

The purpose of the accelerated approval route is to speed up the approval process of promising therapies, so it can reach the market as fast as possible.

CDER/CBER review and determination for product safety and effectiveness will be based on “surrogate endpoints”.

Surrogate endpoints can be laboratory indirect finding or physical signs that can predict an investigational drug’s therapeutic benefit.

6.   NDA

6.1  What is NDA?

The NDA sponsors formal requests to market the drug product in the U.S and it includes pre- clinical and clinical results in addition to manufacturing and labeling information. Pre-NDA meeting will be taken towards phase 3 data analysis and conclusions at NDA submission.

6.2  As mentioned in previous sections, the New Drug Application (NDA) to the FDA includes all information related to the drug product and development process.

6.3  The information below will be detailed in the NDA:

  • Drug product and drug substance description and characteristics
  • Animal and pre- clinical studies data
  • Pharmacology and toxicology data
  • Human pharmaco-kinetic and bioavailability data
  • Human studies and clinical data- safety
  • Two well controlled and appropriate efficacy human studies and supportive evidence data
  • Statistical analysis
  • Pediatric data
  • CMC data (Chemistry, manufacturing and controls)
  • Proposed manufacturing technologies and methods, safe guards, quality assurance (QA) and Good Manufacturing Practices (GMP)
  • Proposed labeling
  • Case reports and data
  • Patent information- In case of exclusiveness (approval will not be delayed by patent or exclusivity rights of other drugs)
  • Debarment certification
  • Clinical investigators financial disclosure

The NDA will be prepared based on 21CFR 314.101(A).

6.4  FDA refusal

FDA Refusal To File (RTF) NDA may be occurred in cases of:

  • Incomplete application
  • Application submission in improper format
  • Omission of clinical data
  • No statement of pre- clinical studies were performed according to GLP (Good Laboratory Practice)
  • No statement that clinical studies included proper informed consent and followed IRB requirements
  • Investigational drug is already covered by another application submitted to the FDA

6.5  NDA review team

NDA review team is responsible for drug approval decision and determines whether the studies completed were controlled and provide substantial evidence of effectiveness and if the product is safe under conditions of usage included on the product label.

NDA review team will be composed of the following staff members:

  • Project manager
  • Medical officer- A physician that will evaluate clinical tests data and adverse effects/events
  • Chemist- Evaluate methods of manufacturing controls, stability and packaging in order to assure the chemical compound is stable and reproducible
  • Microbiologist- Evaluate the microbial results and content and their effect on patients
  • Statistician- Evaluate study design and the validity of the statistical analysis in order to determine the solidity of the findings and to assure findings can be extrapolated to the patient population
  • Pharmacologist- Evaluate animal trials results
  • Establishment/facility reviewer
  • Support personnel- per need

6.6  NDA approval

CDER/CBER approval after NDA review can be one of the following:

  • Approval letter- No need for response
  • Approval letter with minor deficiencies- Require 10 days response from sponsor
  • Non approval letter- Letter with major deficiencies and requires 10 days response from sponsor regarding amend NDA, withdraw NDA or request hearing.

6.7  NDA disapproval

NDA disapproval can be as results of the following:

  • Inadequate testing
  • Inadequate manufacturing and controls- Manufacturing process was not in compliance with cGMP (Current Good Manufacturing Practice) standards and requirements
  • Insufficient safety evidence
  • Inadequate efficacy data
  • Misleading label information
  • False statement

7.   Advisory community

Advisory community is a panel of outside scientific experts that consults with the FDA review team.

Sometimes, per FDA or the sponsor’s request, the advisory community will review the investigational drug product data.

This outside advice exists in order to allow the FDA to benefit from wider national expert input.

Advisory community may include physicians, statisticians, pharmacologists, epidemiologists as well as at least one public representative that will represent the client or patient’s perspective and will raise customer concerns that might not be addressed otherwise before product marketing.

There are open public meetings that should give the public the opportunity for access to information regarding trends in healthcare and to raise public awareness of new public health issues.

CDER/CBER usually agrees with advisory community decisions, but CBER/CDER is not committed to their recommendations.

8.   Supplemental New Drug Applications (sNDA)

Supplemental New Drug Applications (sNDA) can be submitted in the following:

  • Drug label changes
  • New doses for the drug
  • New strengths for the drug
  • New manufacturing process for the drug

CDER and CBER office of compliance is responsible to determine labeling, manufacturing and testing standards, monitor marketed drugs quality, evaluate, classify and recommend drug recalls.

9.   Post marketing surveillance

Office of drug safety is responsible for drug safety after approval, safety information retrieval and adverse events reporting for Drugs, Medical Devices, Biological and Dietary Dupplements. This information can be reported and received via MedWatch website.

Adverse effects can be reported via Adverse Events Reporting System (AERS). AERS include international database.

The Office of Drug Safety (ODS) uses AERS to triage, review and assess the risks of marketed drugs.

In cases of post marketing drug safety problems discovery, the following regulatory actions may be required:

  • Labeling changes
  • Scientific publications
  • Physicians specific warning letters
  • Restricted use
  • Restricted distribution
  • Patient  medication guide
  • Product withdrawal


About the author:

Eran Yona Bio-Chem CEO and GxP consultant