The normal cycle of drug invention goes through a various phase of analysis and testing the drug in the lab and with animals in order to derive final product. It’s like trial and error where initial phase of drug design in Clinical trial undergoes a various level of modification when once it has been into the testing phase. Under normal situation, researchers need to work for around 20-30 years in order to derive new product with very fewer side effects and more health benefits. Check out my previous post on various methods used to design clinical trial-an clinical trial basics.
It’s important for us to understand what exactly happens during these 20-30 years of drug discovery to gain knowledge on the drug we use and to understand the importance of FDA and other agencies in the healthcare industry.
All new invention in the field of healthcare should go through below steps before getting a license to release the product into the market for human consumption.
Step 1 – Drug design:
Based on the available data, researchers create a design to develop a drug to find a solution for the human health problems. In this stage, researchers conduct various experiments in the laboratory to prove their theory of drug design.
Step 2 – Preclinical Research:
Post drug design step, drugs undergo laboratory and animal testing to answer basic questions about the safety of drug on living organisms.
Step 3 – Clinical Trial:
This is the important phase of clinical research in which drugs are tested for its efficiency on the human body. Clinical trials are conducted in 4 main phases (Phase 1 to Phase 4) before moving to next step. Check out my previous post on Clinical trial basics.
Step 4 – FDA Review:
Post Clinical trial, FDA team thoroughly examine all the submitted data related to the clinical trial data of the drug and make a decision to approve or not to approve it.
Step 5 – Post-Market release safety analysis by FDA:
FDA monitors all drugs for safety once products are available for use by the public.
Find out my previous post on FDA Drug safety analysis and approval process
There are few exceptions allowed to the above procedure in which, drug approval process takes short route in order to release the rarest available medicine to the market for the patient’s benefit. The Food and Drug Administration has developed four distinct and successful approaches to speeding the availability of drugs that treat serious diseases:
- Accelerated Approval
- Priority Review
- Breakthrough Therapy
- Fast Track
What is Accelerated Approval?
As per the FDA Accelerated Approval Program 1992 regulation, it allows the institution to fast approve the drug that fills an unmet medical need for serious condition based on a surrogate endpoint. Most of the Accelerated Approved drugs are assigned with a Priority Review designation which is approved using the data from the surrogate intermediate clinical endpoint.
The data for the surrogate endpoint in the Accelerated Approval process is obtained from the Clinical Trial Phase 3. Drugs approved under the FDA Accelerated Approval Program still need to be tested in clinical trials using endpoints that demonstrate clinical benefit, and those trials are known as phase 4 confirmatory trials. If the drug later proves unable to demonstrate clinical benefit to patients, the FDA may withdraw approval.
What is Priority Review?
Under the U.S Prescription Drug User Act (PDUFA), FDA’s goal is to take action on an application within six months (compared to 10 months under standard review) where the agency determines that the drug, if approved, would significantly improve the safety or effectiveness of treating, diagnosing or preventing a serious condition.
Significant improvement may be demonstrated by the following examples:
- Evidence of increased effectiveness in treatment, prevention, or diagnosis of the disease condition.
- Elimination or substantial reduction of a treatment-limiting drug reaction.
- Documented enhancement of patient compliance that is expected to lead to an improvement in serious outcomes or
- Evidence of safety and effectiveness in a new subpopulation.
Fast Track Review:
Fast track review is a type of review available under FDA drug approval process to get important new drugs to the patient earlier. Fast Track addresses a broad range of serious conditions like AIDS, Alzheimer’s, heart failure and cancer etc.
A drug that receives Fast Track designation is eligible for some or all of the following:
- More frequent meetings with FDA to discuss the drug’s development plan and ensure collection of appropriate data needed to support drug approval.
- More frequent written communication from FDA about the design of the proposed clinical trials and use of biomarkers.
- Becomes eligible for Accelerated Approval and Priority Review, if relevant criteria are met.
- Rolling Review, which means that a drug company can submit completed sections of its Biologic License Application (BLA) or New Drug Application (NDA) for review by FDA, rather than waiting until every section of the NDA is completed before the entire application can be reviewed.
Breakthrough Therapy designation is a process designed to expedite the development and review of drugs that are intended to treat a serious condition and preliminary clinical evidence indicates that the drug may demonstrate substantial improvement over an available therapy on clinically significant endpoints. Clinically significant endpoint generally refers to an endpoint that measures an effect on irreversible morbidity or mortality (IMM) or on symptoms that represent serious consequences of the disease.
A drug that receives Breakthrough Therapy designation is eligible for the following:
- All Fast Track designation features.
- Intensive guidance on an efficient drug development program, beginning as early as Phase 1.
- Organizational commitment involving senior managers.
What are Endpoints in Clinical Trials?
In clinical trials, an end point is a series of measurable event or outcome which are expected from an intervention being studied to determine the study as beneficial. The endpoints of a clinical trial are usually included in the study objectives. Some examples of endpoints are survival, improvements in quality of life, relief of symptoms, and disappearance of the tumor.
Surrogate endpoint also known as pseudo endpoint uses a Biomarker as an indicator instead of clinical endpoint to tell if a treatment works. In cancer investigation, Surrogate endpoints include a signs like shrinking tumor or lower biomarker levels which are measured using a laboratory measurement, radiographic image, physical sign or by various other measures.
Surrogate endpoint are used as an alternative to clinical endpoint like longer survival of patients, improved quality of life or slowly decrease in symptoms of the disease to identify the efficiency of the drug.
Surrogate or intermediate clinical endpoints can save valuable time in the drug approval process. For example, instead of having to wait to learn if a drug actually extends survival for cancer patients, the FDA may approve a drug based on evidence that the drug shrinks tumors, because tumor shrinkage is considered reasonably likely to predict a real clinical benefit.
Advantages of Surrogate Endpoint:
- Surrogate endpoint helps in Accelerated Approval of certain drugs in clinical trials to treat serious or life-threatening diseases, such as cancer.
- Surrogate endpoint is used to measure the efficiency of a specific drug that may correlate with a real clinical endpoint.
- Unlike clinical endpoint, Surrogate endpoint helps in faster and cost effective measurement of efficiency of the drug.
Disadvantages of Surrogate endpoint:
- Surrogate endpoint fails provide the possible unfavorable side effects of the drug.
- Surrogate endpoint present substantial risks when clinical trial designers confuse them with clinical endpoints.
- Shorter, smaller studies using surrogate endpoint may not reveal all risks (risk ratio may not be clear).
- Unlike the clinical endpoint, Surrogate endpoint (presence of Biomarkers) sometimes doesn’t correlate with the patients’ clinical state.
- Biomarkers are sometimes undetectable with the standard laboratory methods.
Clinical or Direct endpoint:
Unlike Surrogate endpoint which uses Biomarker, the Clinical endpoint uses the clinically meaningful data obtained from study conducted with human patients post the intervention of drug under study. Clinical endpoint directly measure how a patient feels, functions, or survives post the intervention of drug. This are the final set of data reviewed and analyzed by FDA as a process of standard review and approval of any new drug.
Composite Endpoints are a single measure of effect, based on a combination of individual endpoints which are useful for drugs that can benefit patients in several ways. These endpoints are used in certain clinical trial to minimize the number of patients required during the clinical trial phase of drug test. This method uses the multiple endpoints to measure the efficiency of the drug intervention.
Examples include Cardiovascular death or hospitalization for heart failure, Clinical worsening like categorical decline in functioning, worsening symptoms, addition of a new medication, hospitalization due to the disease, death, etc each adds on to form a combination of the single endpoints.
What is Biomarker?
Biomarker are a biological molecule found in tissues or blood and other body fluids which are objectively measured and evaluated as an indication of normal biologic processes, pathogenic processes, or pharmacologic responses to a therapeutic intervention. A biomarker may be used to see how well the body responds to a treatment for a disease or condition. Also called molecular marker and signature molecule.
Advantages of Biomarkers:
Biomarkers are one of the most vital factors used in clinical research to find the efficiency of drugs. Below are the few other advantages of Biomarkers:
- Biomarkers which are used as a surrogate endpoint of clinical trial helps in an Accelerated Approval of dug for major diseases, such as cancer and heart disease.
- Biomarkers help in homogeneous classification of a disease and its risk factors.
- Understanding the relationship between measurable biological processes and clinical outcomes helps to provide base information about the underlying pathogenesis of disease.
- Understanding the biological structure and its composition of Biomarker of certain disease helps in design and development of drug to the treatments of diseases.
- Biomarkers are easier and cheaper to measure than any other clinical endpoint.
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