RHEOSENSE. INC.

FDA APPROVAL
PRocess

A complete guide to understanding the FDA

drug approval process
Table of Contents
INTRODUCTION

STEP 1: DISCOVERY AND

DEVELOPMENT

STEP 2: PRE-CLINICAL RESEARCH

STEP 3: CLINICAL RESEARCH

STEP 4: DRUG REVIEW

STEP 5: POST-MARKET DRUG SAFETY

MONITORING

CONCLUSION

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fda approval process timeline
"THE FDA IS RESPONSIBLE FOR PROTECTING THE PUBLIC
HEALTH BY ASSURING THE SAFETY, EFFICACY, AND THE
SECURITY OF HUMAN AND VETERINARY DRUGS,
BIOLOGICAL PRODUCTS, MEDICAL DEVICES, THE NATION'S
FOOD SUPPLY, COSMETICS AND PRODUCTS THAT EMIT
RADIATION" (FDA)

STEP TIMELINE (APPROXIMATE)

STEP 1
3 - 6 YEARS
DISCOVERY & DEVELOPMENT

STEP 2
1 - 2 YEARS
PRE-CLINICAL RESEARCH

STEP 3
3 - 9 YEARS
CLINICAL RESEARCH

STEP 4
6 - 10 MONTHS
DRUG REVIEW

The average time from FDA application to approval of drugs is 12 years, and the estimated average
cost of taking a new drug from concept to market exceeds $1 billion. (Science Direct)

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Step 1:
Discovery & development

In discovery and development, researchers set a goal to stop or

reverse an ailment or disease. In this stage of drug development,
researchers will test hundreds or even thousands of different
RESEARCHERS
compounds and eventually identify a handful for further study.
CAN START WITH After identifying feasible compounds, researchers can then begin
THOUSANDS OF to design how to conduct the experiments to test:

COMPOUNDS AS How it is absorbed, distributed, metabolized, and excreted

POTENTIAL Potential benefits and mechanisms of action
The optimal dosage
CANDIDATES IN The best way to give the drug (such as by mouth or injection)
EARLY TESTING. Side effects or adverse events
How it affects different groups of people
How it interacts with other drugs and treatments
Its effectiveness as compared to similar drugs

Source: fda.gov

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Viscosity in Discovery &
Development
Viscosity can be used in early stage Benefits of Automation
candidate selection to identify which drugs
will likely cause issues in manufacturing
In this stage of discovery & development,
and production down the road.
you are likely to spend a substantial
amount of time measuring samples/
Identifying and predicting viscosity in drug
dilutions, repeating each dilution, and
formulations at this stage can save a distinguishing small incremental changes
tremendous amount of time and resources. in viscosity.

Due to the vast set and compounds at this

stage, automation and high through-put
measurements are essential in expediting
research.

VROC In Discovery &

development
The VROC platform allows for extremely small
volume sample screening and non-destructive
recovery of early stage samples. Additionally, the
instrumentation is sensitive enough to obtain
intrinsic viscosity and hydrodynamic radius.
Sizing is crucial for modelling and fully
understanding your unique molecules. This With the VROC® Initium one plus, you
orthogonal approach to common light scattering are able to measure up to 96 samples at
techniques can eliminate errors and probe into a time with complete automation.
complex conjugate molecules with greater Equipped with cleaning protocols and
accuracy. Intrinsic viscosity is determined by accessible parameters, you are
measuring sample viscosities at increasingly guaranteed to save a tremendous
dilute concentrations, which in stride requires an amount of time which in time will bring
instrument capable of accurately detecting small a greater return on investment.
differences in viscosity between samples.

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Step 2:
preclinical research
AFTER FORMULATING THE
COMPOUNDS REQUIRED IN
DRUG DISCOVERY AND
DEVELOPMENT (STEP 1 OF FDA
APPROVAL), THE NEXT STEP IS
TO THOROUGHLY TEST
EFFICACY AND INJECTABILITY
IN PRECLINICAL RESEARCH.
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The main objective in preclinical research
aims to test whether the drug has the
potential to cause harm to people — in
other words testing the toxicity.
Researchers must follow good laboratory
practices (GLP) which set the basic
requirements for a number of categories
such as written protocols, operating
procedures, facilities & equipment, and
much more (click here for more details).
 Viscosity in the drug
development process
Injectability

At this stage of preclinical research and testing, experiments are designed to

maximize the drug concentration per dosage while maintaining and optimizing
efficacy. For the model drug, at high concentrations and shear rate, viscosity can
decrease. Therefore, the shear rate at the wall of the needle would be higher than
that of the Newtonian liquids at the same flow rate.

Smaller injection volumes are convenient for both developers and patients.
Injectability is a critical component of research in drug development because drug
delivery by injection must account for high shear-rate and yield consistent batches
and a consistent product.

When necessary, there will be minor to major changes to the formulations as

adjustments are made. Meaning there is an iterative approach to any formulation.

Applications

Drug injections require a perfect balance between efficacy and pain tolerance for
the end user. The goal is to provide a seemingly painless experience for both the
user and the administrator without sacrificing the drug efficacy. To achieve this, the
rate of injection must be tested to find the balance between efficacy and pain
tolerance. If the drug is of high viscosity, injection at higher shear rates may be
more painful, while on the other hand if the dosage is not concentrated, the drug
will not be as effective.

So why measure?

Checking viscosity for injectability is critical at this stage of research, as most protein
therapeutics tend to be shear thinning. High viscosities of candidate drugs can lead
to disqualification or costly development of alternative delivery methods, due to the
difficulty of injection for high viscosity medications or causing patient pain during
administration. Because of these challenges caused by higher viscosities, drug
stability in mAb formulations must be achieved with the lowest viscosity values
possible. Measuring viscosity can also assist determining particle sizing research
during this stage of research.

Small sample volume viscosity measurement is especially important at early stage

development as candidate drugs are often available only in small quantities.

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Step 3:
clinical research

The clinical research stage is designed to

gather information and factors that affect
the drug's response on the human body.
Researchers will review prior information
CLINICAL TRIALS ARE and other objectives to decide who is
qualified to participate, how the drug will
DESIGNED TO ANSWER be administered, how the data will be
SPECIFIC RESEARCH analyzed, and much more. Clinical trials
QUESTIONS AND FOLLOW A typically follow a series of phases to
TYPICAL SERIES FROM EARLY, indicate progress and different purposes
and goals. For example, phase 1 studies
SMALL-SCALE TO LATE-STAGE, may have a small sample of participants
LARGE SCALE STUDIES and usually aim for safety while phase 4
studies have several thousand volunteers
who have the disease or condition while
aiming to test safety and efficacy (example
found here).

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clinical trial sub-phases
PHASE ESTIMATED BUDGET

20 – 100 study participants and lasts several months. This phase is

PHASE 01 used to determine the safety and dosage of the drug, and about
70% of these drugs move on to the next clinical research phase.

Up to several hundred people, who must have the disease or

condition the drug supposes to treat. This phase can last from a
PHASE 02 few months to two years, and its purpose is to monitor the efficacy
of the drug, as well as note side effects that may occur. About 33%
of drugs move on to the next clinical research phase.

300 – 3000 volunteers and can last up to four years. It is used to

PHASE 03 continue monitoring the efficacy of the drug, as well as exploring
any longer-term adverse reactions. About 25-30% of drugs move
on to the next clinical research phase.

Several thousands of volunteers who have the disease or

PHASE 04 condition and continues to monitor safety and efficacy. If a drug
passes this phase, it goes on to FDA review, however only ~14% of
drugs reviewed win FDA approval.

Source: https://diabetespac.org/

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viscosity in clinical
research
Setting Parameters So why measure
for Testing viscosity?
After passing preclinical trials,
Drug stability is one of the most
the drug will be replicated in
important factors in clinical
various scales for production
testing. Temperature and
with different concentrations
efficacy serve as a function over
under meticulously set
time to ensure the drug is
conditions for group
consistent under various
experimentation. There are
conditions. When testing
three major factors that are
stability as a function over time,
taken into consideration when
pH levels, concentration, and
measuring the components of
viscosity are highly likely to be
the drug:
tested to detect any noticeable
changes.
1. S t a b i l i t y
2. P r o d u c t i o n
During lot production, fluid
3. G r o u p t e s t i n g
measurements need to be
exactly the same as all the
Prior to production, stability of
others. Consistency and stability
the drug must be thoroughly
needs to be precisely
tested to ensure the drug stays
monitored. In addition, scaling
consistent under various
up production due to
circumstances including time
manufacturing sites and
and temperature. Assuming
methods require extensive
concentration and dosage levels
protocols for viscosity
are measured correctly in
measurement.
preclinical trials, the drug is
now ready to be tested with a
If viscosity is not measured,
human control group.
manufacturing and scaling up
production could face various
issues. Factors include new
machinery to accommodate for
large-scale production which
can alter the drug compounds
as a result of interacting with
different mixture methods or
higher pressures. Another
indication of viscosity issues is
inaccurate fill volumes

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Step 4:
fda drug review

Once a New Drug Application (NDA) is

filed, an FDA review team will evaluate the
THE FDA REVIEW TEAM data submitted from clinical studies to
CONSISTS OF MEDICAL determine if the drug is safe and effective.
DOCTORS, CHEMISTS, When reviewing "safety" of a drug, the FDA
looks for evidence that the drugs benefits
STATISTICIANS, outweigh the known risks associated with
MICROBIOLOGISTS, the drug, The FDA review team has 6-10
PHARMACOLOGISTS, AND months to make a decision on whether
OTHER EXPERTS WHO they will approve the drug or not.

EVALUATE DRUG SAFETY AND Only ~10% of drugs that start Phase I
EFFECTIVENESS FOR ITS clinical trials receive FDA approval.
PROPOSED USE. (gao,gov)

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 fda drug review steps
BEFORE AWAITING APPROVAL

Before submitting the finished drug for approval to the U.S. Foods and Drugs
Administration, a New Drug Application (NDA) must be submitted. The NDA
provides the blueprint of the drug and outlines the purpose, efficacy, and ultimately
demonstrates the overall safety upon application. Additional requirements for
submission include:

All data from preclinical stage to Phase 3 clinical trials

Proposed labeling
Any data from studies that may have been conducted outside the United States
Institutional review board compliance information

REVIEW
Once the NDA application is submitted, the FDA has 60 days to decide whether they
choose to accept or deny the application if it is unable to meet all criteria for
requirements. The review process can last anywhere between 6 to 10 months
depending on the NDA application and whether it requires further investigation.
The process is outlined as follows:

1. The FDA team will review the full application. Each member of the team is
assigned to a section of the application for meticulous examination.
2. The FDA inspector then visit the clinical study sites for routine inspection. The
inspection will account for any evidence of tampering/manipulation, fabrication,
or withholding of data.
3. After each section of the application has been thoroughly investigated and
examined, review documents and inspection reports are compiled into what is
called an action package. The review team then issues a formal
recommendation to a senior FDA official who then makes the final decision.

APPROVAL

During examination and careful consideration, the FDA will determine whether the
drug has demonstrated efficacy for its intended use and more importantly have
been proven to be safe for public consumption. If all criteria is met, the FDA works
with the applicant to develop and refine prescribing information, a process known
as 'labeling' (FDA). Labeling aims to be absolutely error-proof and has to be accurate
as possible as it provides the guidelines on how to use/consume the drug.

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Step 5:
Post-Market Drug Safety
Monitoring
AFTER OBTAINING APPROVAL
FROM THE U.S. FOODS AND
DRUGS ADMINISTRATION, THE
PRODUCT WILL BE AVAILABLE
FOR THE GENERAL PUBLIC. THE
FDA WILL CONTINUE TO
MONITOR ALL ACTIVITY AND
THE DRUG SPONSOR IS
REQUIRED TO SUBMIT PERIODIC
SAFETY UPDATES TO THE FDA.
SOURCE: FDA.GOV
Although the review process may have
evaluated and cleared the drug, there are
limitations for absolute safety guarantees
because of the extensive amount of
information and time constraints. Thus
after approval, the FDA will continue to
monitor and take reports of any issues or
problems with the drug over the coming
months and years to add cautions and/or
warnings regarding dosage information or
any other issues they may encounter that
were not evident during steps 1 through 4.
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Safety Monitoring
& Adjustments
In the coming months, the FDA reviews any problems or reports of incidents
related to the new product. They can determine whether to add any adjustments
to dosage or additional precautions to the product when necessary. The FDA has
various databases that provide reports of consumer data and other possible safety
issues. Some of the programs that provide consumer reports to the FDA are listed
below:

MedWatch - Problems regarding medical products and new safety information

are reported (FDA).
Medical Product Safety Network (MedSun) - Actively monitors the safety and
effectiveness of medical devices (FDA).
Sentinel Initiative - A vast network of databases that incorporates electronic
health records systems, administrative and insurance claim databases, and
registries (FDA).

role of viscosity
In the post-market stage, viscosity
still plays a vital role in the
production and maintenance of
drug manufacture. Essentially
monitoring manufacturing methods
and continuing to ensure all the
RheoSense offers a variety of viscometers that measure
products are falling within
viscosity under high-throughput capabilities under
specifications upon production.
various shear rates. Your research and criteria is a
Even more so when scaling up
uniquely tailored application, see which VROC®
production, as new machinery has instrument is right for you.
the potential to alter fluid
characteristics when increasing microVISC™ - Portable, small sample viscometer
pressure or forces. Measuring m-VROC ® - Small sample, controlled shear rate
viscosity is imperative when viscometer
ensuring every batch is identical to VROC ® initium one plus - Fully automatic, small
the next and making sure quality sample viscometer with controlled shear rate with
control is up to standards. sample retrieval

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conclusion
FDA APPROVED MEDICATION IS DESIGNED TO ENSURE THAT THE
BENEFIT OF AN APPROVED DRUG OUTWEIGHS THE POTENTIAL
NEGATIVE EFFECTS. TO SUCCESSFULLY OBTAIN FDA APPROVAL, THE
DRUG DEVELOPMENT PROCESS IS SCRUTINIZED AT EVERY STEP FROM
DISCOVERY AND DEVELOPMENT TO POST-MARKET SAFETY
MONITORING.

Understanding the need for measuring

viscosity in drug formulation at early stage
development can prevent project elimination
in late stage approval and save tremendous
amounts of time and resources. Due to the
vast and endless possibilities of various
compounds and solutions, it is prudent to
measure viscosity early on to expedite
research so you can move to step two: pre-
clinical research. The various stages in the
drug approval process constitute for
different methods and reasons in measuring
viscosity. Measuring viscosity is relevant at
each stage of the FDA drug approval process.
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COMPANIES AND SCIENCE
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ASSIST AND EXPEDITE DRUG
DISCOVERY & PRECLINICAL
TESTING. IF YOU HAVE ANY
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US AT RHEOSENSE.COM OR EMAIL
US AT INFO@RHEOSENSE.COM

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