Lecture 3 - drug discovery and approval

Question 1

Who approves drugs?

Answer 1

The Food and Drug Administration (FDA)
The Center for Drug Evaluation and Research (CDER)
Center for Biologics Evaluation and Research (CBER)
Center for Devices and Radiological Health (CDRH)
Center for Food Safety and Applied Nutrition (CFSAN)
Center for Veterinary Medicine (CVM)

Question 2

New Drug Development and Approval Summary

Answer 2

Question 3

Definition of a drug

Answer 3

“A drug is a substance that exerts an action on the structure of function of the body by chemical action or metabolism and is intended for use in the diagnosis, cure, mitigation, treatment, or prevention of disease.”

Question 4

Definition of a “new” drug

Answer 4

“A new drug is defined as one that is not generally recognized as safe and effective (GRASE) for the indication proposed.”

Question 5

Drug Discovery and Development Process

Answer 5

1.) Identification of an active ingredient or NME (New Molecular Entity)
2.) Proper manufacture of the product
Conduct of scientific tests
- Preclinical
- Clinical
3.) Marshaling of data collected from those tests

The objective is to provide evidence to prove that the drug is effective for its indicated uses, that the risks associated with that drug are known on the basis of reasonable testing, and that the nature of the known risks is appropriate with the anticipated benefit for the indication.

Question 6

FDA’s procedures

Answer 6

Current Good Manufacturing Practices (cGMPs)
Good Laboratory Practices (GLPs)

Question 7

Identification process of Active Ingredient or NME

Answer 7

1.) Discovery of a chemical compound
-Compound-Centered Drug Discovery
—Producing compounds that were tested on biological targets (primarily) receptors
— Compounds were typically endogenous to the body or found in nature

2.) Target-Centered Drug Discovery
Chemical compounds were designed to hit a specific target
- Target-based therapies
- Gene-based therapies
3.) Serendipity

Question 8

Finding the right match between the target and chemical compound is achieved through:

Answer 8

1.) De novo - Rational drug design (starting from scratch)
2.) High-throughput screening
3.) Combinational chemistry
4.) Serendipity

Question 9

The right drug match is called a _______

Answer 9

LEAD COMPOUND

Question 10

Hundreds of manipulations to get the lead compound are made to…

Answer 10

• Maximize receptor affinity
• Improve pharmacokinetic properties

Question 11

What does preclinical investigation consist of?

Answer 11

A group of Pharmacodynamics, Pharmacokinetics (ADME) and Toxicology testing to assess potential therapeutic effects of the NME on living organisms and to gather sufficient data to determine its reasonable safety in human through laboratory experimentation and animal investigation.

Takes 1 to 3 years

No prior approval for investigator and pharmaceutical industry sponsors is required to begin a preclinical evaluation.

Question 12

In the preclinical investigation phase, what must be followed?

Answer 12

Follow GLPs that govern laboratory facilities, personnel, equipment, and operations.

Compliance of GLP requires procedures and documentation of training, study schedules, processes, and status reports that are submitted to FDA for approval for clinical investigations.

Question 13

Clinical investigation - Drugs studied in a clinical trial are called investigational drugs and are part of ________

Answer 13

the Investigational New Drug (IND) application.

Question 14

Clinical Trials are designed in phases to:

Answer 14

• Establish the efficacy and safety of the drug
• Protect the health and safety of human test subjects
• Ensure the integrity and usefulness of the clinical study data

Question 15

Questions the Clinical Process should answer:

Answer 15

• Does the drug have the effect it is supposed to have
• How much of the drug to give and how often should it be given?
• What side effects are associated with the drug and can they be managed?
• How is the drug broken down and how long does it stay in the body?
• Which foods, drinks, or other drugs can be used at the same time or should be avoided?

Question 16

What must be done with the IND Application?

Answer 16

Sponsor must submit IND to FDA.
- Cover sheet, table of content, introductory statement and investigation plan, brochure, protocols, NME’s chemistry, manufacturing and controls, pcol/tox info, any previous human experience with the NME, others.

After submission, wait for 30 days before commencing trials.
- FDA does not “approve” an IND, if FDA does not object within 30-day period, the trials may begin.

Question 17

Ground rules for clinical trials

Answer 17

Clinical study protocol must be developed by sponsor, reviewed and approved by an IRB (Institutional Review Board).
- IRB oversees the research to protect human test subject rights as well as maintains rigorous medical and scientific standards.
- IRB must also review and approve informed consent documents prior to commencing the trials.
— Participants must be informed adequately about the risks, benefits and treatment alternatives before participation in the trials.

All these documents should be open to FDA inspection at any time.

Question 18

Clinical trial design

Answer 18

Gold Standard is DBRCT
- Double blind randomized controlled trial

Bias and confounding factors occur
- The key is to minimize these items
- Want to be sure that the results are a result of the intervention

Randomization
- Have more than one intervention
- Participants are assigned to one of the intervention groups randomly.
- Ensure that composition is identical
- Should not be known by patient, MD, drug company personnel, etc.

Blinding
- Reduces being influenced by knowledge
- Strategies employed:
— Make all activities identical
— Make all treatment items identical

Statistics – SAMPLE SIZE
- The study should identify a primary outcome(s)
- Statistical Power is the calculation of the sample size. The key is to have a sufficient sample size to reach a conclusion regarding the outcome.
— Want to be sure that if there is a difference between interventions, it can be revealed statistically.
- COMPARISONS: superiority, noninferiority, and equivalence.
— Superiority design- comparison with a placebo
— Noninferiority design – confirms that one intervention IS NOT inferior to a comparator
— Equivalence design – determines whether one intervention is statistically no different in effectiveness than another.

Efficacy Data
- Continuous – interval, ration, mean difference
- Dichotomous – all or none items
— Only two categories or levels, e.g., male or female; yes, or no
- Expresses as:
— Relative Risk Reduction (RRR)
— Absolute Risk Reduction (ARR)

Question 19

Clinical Trial Data Analysis

Answer 19

Safety Data
- Adverse Event
- Serious Adverse Event
- The number needed to harm (NNH)
- The number needed to treat (NNT)

Meta-Analysis
- A quantitative, formal, study design used to systematically assess previous research studies to derive conclusions about that body of research

Question 20

IND – Phase I

Answer 20

• Establishes the PK profile, safety and dosage
• Uses healthy volunteers (w/o the dx)
• Open label
• Fast-tract conditions allows for persons with the dx to be a part of the study
• Study size – small, less than 100 subjects
• Duration – short (couple of doses, one year or less)
• Results used to develop Phase II

Question 21

IND – Phase II

Answer 21

• First controlled clinical trial to establish the PK profile, safety and efficacy
• Phase IIa is the pilot study to determine initial efficacy
• Phase IIb is the controlled study
• Single or double blinded
• Fast-tract conditions allows for persons with the dx to be a part of the study
• Study size – medium, several hundred subjects
• Duration – weeks to months

Question 22

IND – Phase III

Answer 22

-Establishes the PK profile, safety and efficacy, final formulation, indications, labelling, marketing claims, product stability and packaging and storage conditions
- Double-blind
- Study size – large
- Duration – months to years
- THIS IS THE FINAL STAGE BEFORE DRUG APPROVAL.
- Notice of Compliance is filed with FDA to determine whether a drug is approved for widespread use.
- New Drug Application (NDA)

Question 23

IND – New Drug Application (NDA) - goals and letter response

Answer 23

The goals of NDA are to provide enough information to permit the FDA reviewer to determine whether:
- The drug is safe and effective for proposed indications and its benefits outweigh the risks
- The package insert is appropriate
- The manufacturing and quality control methods are appropriate to preserve the drug’s identity, strength, quality and purity

Then the FDA reviewer will provide their action letter, which could be one of following three:
- Approval letter – all requirements are met, and the company can begin marketing the drug
- Approvable letter – some minor deficiencies, which must be addressed before approval letter
- Nonapprovable letter – major concerns with the application

Question 24

Special Processes with IND – New Drug Application (NDA)

Answer 24

Fast Track
- Facilitate the development and expedite the review of drugs to treat serious diseases (e.g., AIDS, Alzheimer’s, heart failure, cancer) and fill an unmet medical need
- Either no therapy exists, or providing better alternative
- Priority review and rolling review

Accelerated Approval
- Allowing earlier approval of drugs to treat serious diseases that fill unmet medical need based on surrogate endpoint (e.g., survival or symptom improvement)
- Post marketing clinical trials should verify the clinical benefits

Priority Review
- Prescription Drug User Fee Act (PDUFA; 1992), FDA created a two-tiered system of review times – Standard Review and Priority Review. - A Priority Review means an application will be reviewed within 6 months (compared to 10 months under standard review).
A Priority Review designation is for drugs that would provide significant improvements in the safety or effectiveness of the treatment, diagnosis, or prevention of serious conditions when compared to standard applications.

Breakthrough Therapy Designation
- A process designed to expedite the development and review of drugs to treat a serious condition with preliminary clinical evidence suggesting substantial improvement over available therapy on a clinically significant endpoint(s).
- a Breakthrough Therapy designation request should be received by FDA no later than the end-of-phase-2 meetings

Question 25

Phase IV and Postmarketing Surveillance

Answer 25

Ensure safety after widespread distribution

This phase is not required, but FDA may require it for fast-track provisions
- Surveillance, double-blind
- Study size – very large
- Duration - years

Question 26

Adverse Event Reporting System

Answer 26

FAERS is the FDA’s Adverse Event Reporting System

It’s a database containing received adverse event and medication error information post-marketing.
- FAERS is a useful system for looking for new safety concerns, evaluating a manufacturer’s compliance to reporting regulations and responding to outside requests for information.
— If a potential safety concern is identified in FAERS, further evaluation is performed.
— FDA may take regulatory action(s) to improve product safety and protect the public health, such as updating a product’s labeling information, restricting the use of the drug, communicating new safety information to the public, or, in rare cases, removing a product from the market.

Reporting of adverse events and medication errors by healthcare professionals and consumers is voluntary in the United States.
- Healthcare professionals and consumers may also report adverse events and/or medication errors to the products’ manufacturers.
— If a manufacturer receives an adverse event report, it is required to send the report to FDA. The reports received directly and the reports from manufacturers are entered into FAERS.

Question 27

FDA’s Sentinel Initiative

Answer 27

Launched in May 2008, the Sentinel Initiative is the national electronic system designed to monitor the safety of FDA-regulated medical products, including drugs, vaccines, biologics, and medical devices.
- Proactively monitors the safety of medical products after they have reached the market.
- Designed to complement the FDA’s existingAdverse Event Reporting System.

FDA can rapidly and securely access information from large amounts of electronic healthcare data (EHR, insurance claims data and registries, from a diverse group of data partners.
- Sentinel uses a distributed data approach which allows the FDA to monitor the safety of regulated medical products, while securing and safeguarding patient privacy.

Question 28

Other Drugs/Products/Procedures

Answer 28

Orphan Drugs
Generic Drugs – Abbreviated NDA (ANDA)
OTC Regulations
Biologics
Devices
Regulating Drugs and Device Marketing

Question 29

Orphan Drugs

Answer 29

Drugs used to treat rare diseases affecting fewer than 200,000 people in the US
- Manufacturer has no reasonable expectation of recovering the cost of development
- Orphan Drug Act 1983 permits grant assistance for clinical research, tax credits for R & D and 7-year market exclusivity to the first applicant

Question 30

Abbreviated New Drug Application (ANDA)

Answer 30

• ANDA are used to market generic drugs to provide a safe, effective, lower cost alternative to the brand-name drug
• In the US, a drug patent is valid for 20 years
• All approved brand and generic drug products are listed in FDA’s Approved Drug Products with Therapeutic Equivalence Evaluations (Orange Book)
• ANDA does not require preclinical (animal) and clinical (human) data. However, must scientifically demonstrate “bioequivalence” through the rate of absorption, or bioavailability, of the generic drug, which can then be compared to that of the innovator drug (20% variation is acceptable). To be approved by FDA, the generic version must deliver the same amount of active ingredients into a patient’s bloodstream in the same amount of time as the innovator drug.

Question 31

OTC Regulations

Answer 31

Principle of OTC status: wide margin of safety, method of use, benefit to risk ration, adequacy of labeling for self-medication
- The OTC Drug Review(4 phases) by advisory panels selection → expert recommendations to Federal Register → public comments → final criteria by FDA
— Can be amended by Citizen Petition and Time and Extent Application (TEA)

OTC products will not fall under prescription status if FDA deem it to be GRASE (Generally Recognized As Safe and Effective)
Category I: GRASE
Category II: not GRASE
Category III: cannot determine if safe and effective

Question 32

What are Biologics

Answer 32

Derived from living organisms: vaccines, antitoxins, serums, blood, blood products, therapeutic protein drugs derived from natural sources (antithrombin III), biotechnology product, gene or somatic cell therapies etc.

Require Biologics License Application (BLA)
- CBER deals with BLA
- Biologics are treated and tested differently than drugs because of composition

Question 33

Devices

Answer 33

Any devices with therapeutic claim ranging from toothbrush to cardiac stent are under FDA’s jurisdiction.

CDRH is responsible for all regular and radiation emitting devices
- Class I, II, III depending on severity of risk

Question 34

Regulating Drug and Device Marketing - All promotional information must ______

Answer 34

be truthful, fairly balanced, and fully disclosed

Question 35

Violations and Enforcement

Answer 35

FDA has the jurisdiction to inspect manufacturer’s premises and records
Enforcements may include:
- Warning letter
- Recall
— Class I: if product is seriously harmful
— Class II: if product causes temporary or medically reversible
— Class III: if product is not likely to cause adverse effects
- If company does not comply with recalls, FDA may seek injunctions against them to the DOJ
- Seizure of violative products

Question 36

Limitations to Drug Approval Process

Answer 36

• FDA does not compare competing drugs and rarely requires tests of clinical efficacy for new devices
• FDA does not review advertisements, assess cost-effectiveness, or regulate surgery (except for devices)
• Postmarketing surveillance of drugs and devices may be inadequate
• Pressure for speedy approvals may result in compromise in safety and/or efficacy
• The agency is unnecessarily slow and bureaucratic
• Conflicts of interest (stock ownership, consulting fees, research grants) among some members of the FDA’s advisory committees

Question 37

Absolute and Relative Risk Reduction

Answer 37

The event rate is the proportion of a population experiencing a particular event.
- Changes according to baseline risk
- Dependent on disease and risk factors

RRR
ARR

Question 38

define event rate

Answer 38

The event rate is the proportion of a population experiencing a particular event.
- Changes according to baseline risk
- Dependent on disease and risk factors

Question 39

Define RRR

Answer 39

The RRR is the difference in event rates between two groups, expressed as a proportion of the event rate in the untreated group.
- For example, if 20% of patients die with treatment A, and 15% die with treatment B, the RRR is 25%. If the treatment works equally well for those with a 40% risk of dying and those with a 10% risk of dying, the ARR remains 25% across all groups.

Question 40

Define AAA

Answer 40

The ARR is the arithmetic difference between the event rates in the two groups. This varies depending on the underlying event rate, becoming smaller when the event rate is low, and larger when the event rate is high.
- In the example above, there is a 5% absolute risk reduction with treatment B if the event rate is 20%. However as the event rate increases to 40%, the absolute risk reduction increases to 10%. As the event rate decreases to 10%, the absolute risk reduction decreases to 2.5%. The treatment still works just as well, but the numbers have changed.