Clinical trials and clinical investigations
Informed consent should be obtained from study participants and submitted according to 21 CFR Part 50 to confirm that volunteers’ participation is truly voluntary and to verify proper disclosure of risks, potential benefits and other alternatives to study subjects.
The IRB (Institutional Review Board) of the center(s) where the study is to be conducted will review and monitor the study in order to protect the subjects participating in the clinical trial.
Clinical investigations should follow FDA 21 CFR Part 312.32 and 21 CFR Part 12 sub-part B, which detail how sponsors should report adverse effects/events, how they should control, distribute and return investigational drug products, and how to assure sponsor investigations are done according to proper protocols, and according to appropriate documentation and implementation practices.
After the clinical trial is competed, the results are collected and analyzed. Afterwards, the sponsor will submit all relevant data to the relevant FDA center in a New Drug Application (NDA) or a Biologics License Application (BLA), including the whole history of the investigational drug product studies and the results. Data will include all relevant data from animal studies, human studies manufacturing and labeling data.
Within 60 days, the FDA will respond to the sponsor to notify if the NDA (or BLA) is accepted for review. The FDA will, in the course of its review, determine if the drug will be approved.
For accelerated approval drugs, detailed in the next section, FDA review will take up to 6 months.
The application’s final destination for review at CDER is determined based on the therapeutic indication of the investigational new drug product. The application will be assigned to the relevant drug product division in CDER (ODEs I, II, III, IV, V, VII).
Before CDER applies their scientific and technical expertise to review the application, they will decide the type of application review that determines the review process timelines:
Standard review is for drugs that appear to have therapeutic qualities similar to those already marketed.
Priority review is for drugs that appear to have an advantage over available therapy, if any exists.
Investigational drug accelerated approval
When no treatment already exists for treatment of a life-threatening disease, new drugs for that indication considered to have “exceptional promise” may receive accelerated (priority) review and approval, or be eligible for CDER or CBER early access programs.
The purpose of the accelerated approval route is to speed up the approval process of promising therapies, so they 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 indirect laboratory findings or physical signs that are predictive of an investigational drug’s therapeutic benefit.
What is an NDA?
An NDA (New Drug Application) is the formal mechanism for requesting approval to market a drug product in the US. It includes preclinical and clinical results, in addition to manufacturing and labeling information. Pre-NDA meetings may be scheduled close to phase 3 data analysis and clinical conclusions are presented in the NDA submission.
As mentioned in previous sections, an FDA NDA includes all information related to the drug product and its development process.
The information below will be detailed in the NDA:
- Drug product and drug substance description and characteristics
- Animal and preclinical studies data
- Pharmacology and toxicology data
- Human pharmacokinetic and bioavailability data
- Human studies and clinical data on safety
- (At least) two well-controlled and appropriate efficacy human studies and supportive evidence data
- Statistical analysis
- Pediatric data
- CMC (chemistry, manufacturing and controls) data
- Proposed manufacturing technologies and methods, safeguards, quality assurance (QA) and good manufacturing practice (GMP)
- Proposed (draft) labeling
- Case reports and data
- Patent information; in case of exclusivity, approval will not be delayed by patent or exclusivity rights of other drugs
- Debarment certification
- Clinical investigator financial disclosure forms
The NDA will be prepared based on 21 CFR 314.101(A).
An FDA Refusal To File (RTF) NDA may be issued in cases of:
- Incomplete application
- Application submission in improper format
- Omission of clinical data
- No statement that preclinical studies were performed according to GLP (Good Laboratory Practice)
- No statement that clinical studies included proper informed consent and followed IRB requirements
- an investigational drug is already covered by another application submitted to the FDA
NDA review team
The NDA review team is responsible for drug approval decisions and it determines whether the studies completed were controlled and provide substantial evidence of effectiveness, and if the product is safe under the conditions of use described on the product label.
The NDA review team is composed of the following staff members:
- Project manager
- Medical officer, a physician who will evaluate clinical test data and adverse effects/events
- Chemist, who will evaluate the methods of manufacturing controls, stability and packaging to assure the chemical compound is stable and reproducible
- Microbiologist, who will evaluate the microbial results and content and their effect on patients
- Statistician, who will evaluate study design and the validity of the statistical analysis to determine the solidity of the findings and to assure findings can be extrapolated to the patient population
- Pharmacologist, who will evaluate animal trials results
- Establishment/facility reviewer
- Support personnel as needed
CDER/CBER approval after NDA review can granted in one of the following ways:
- Approval letter – No need for response from the sponsor
- Approval letter with minor deficiencies – Requires a response within 10 days from the sponsor
- Non-approval letter (complete response letter) – Letter from FDA listing major deficiencies; requires a response within 10 days from sponsor to amend or withdraw the NDA, or to request a hearing.
NDA disapproval can result from the following:
- Inadequate testing
- Inadequate manufacturing and controls, manufacturing process not compliant with cGMP (current good manufacturing practice)
- Insufficient safety evidence
- Inadequate efficacy data
- Misleading label information
- False statements
(Scientific) advisory board
An FDA advisory board is a panel that includes external scientific experts and consults with the FDA review team.
Sometimes, per FDA or sponsor request, an advisory board will review the investigational new drug product data.
This outside advice exists to allow the FDA to benefit from wider national expert input.
Advisory boards may include physicians, statisticians, pharmacologists, epidemiologists, and at least one representative from the public who will represent the client or patient perspective and will raise customer concerns that might not be addressed otherwise prior to product marketing.
There are open, public meetings that give the public the opportunity to access information about trends in healthcare, and raise public awareness of new public health issues.
CDER/CBER usually agree with advisory board recommendations, but CBER/CDER are not committed to or required to abide by them.
Supplemental New Drug Applications (sNDA)
Supplemental New Drug Applications (sNDA) can be submitted in the following situations:
- Drug label changes
- New doses for the drug
- New strengths for the drug
- New manufacturing process(es) for the drug
The CDER and CBER Office of Compliance is responsible for determining labeling, manufacturing and testing standards, monitoring marketed drug quality, evaluating, classifying and recommending drug recalls and market withdrawals.
The Office of Drug Safety (ODS) is responsible for drug safety after approval, safety information retrieval and adverse event reporting for drug and biological products, medical devices, and dietary supplements. This information can be reported to and viewed on the FDA MedWatch website.
Adverse effects can be electronically reported via the Adverse Events Reporting System (AERS). AERS includes international database information.
The ODS uses AERS to triage, review and assess risks of marketed drugs.
When postmarket drug safety problems are discovered, the following regulatory actions may be required:
- Labeling changes
- Scientific publications
- Physicians specific warning letters
- Restricted use
- Restricted distribution
- Patient medication guide
- Product withdrawal