RX 361: Topic 5

Drug Discovery and Development Timeline

1. Drug Discovery

2. Preclinical

(3-6 year)

3. IND Submitted

4. Clinical trials

--- Phase 1

--- Phase 2

--- Phase 3

(6-7 years)

5. NDA Submitted

6. FDA Review (One FDA Approved Drug)

7. Scale-Up to Mfg.

(0.5-2 years)

8. Post-Marketing Surveillance (Phase 4)

(Indefinite)

What are pre-clinical trials?

Animal testing (ex. Mice, rats, rabbits, etc.)

What is determined during pre-clinical trials?

Certain toxicities

1. Does it cause cancer?

2. Does it mutate genes?

3. Does it cause infertility?

Toxicology

the study of the adverse effects of chemical substances on living organisms

IND

Investigational new drug application

Investigational new drug application acronym?

IND

Where does the IND go to?

goes to FDA's Center for Drug Evaluation and Research (CDER)

CDER

Center for Drug Evaluation and Research

What is the acronym for FDA's Center for Drug Evaluation and Research?

CDER

IND includes results of what?

pre-clinical testing and proposal for human testing

CDERs goal is to do what?

to protect who participate in clinical trials from unreasonable and significant risk

Two possible results of CDER review

1. FDA indicates proposed clinical studies are safe to proceed

2. FDA issuance of "clinical hold" - no clinical studies can be conducted

Investigational new drug application

An application that must be submitted to the FDA before a drug can be studied in humans.

Clinical Trials

experiments that study the effectiveness of medical treatments on actual patients

Typical number of healthy individuals used in Phase 1 of clinical trials

20-80 people

What does Phase 1 of clinical trials emphasize?

This phase emphasizes safety

What is the goal of Phase 1 of clinical trials?

To determine what the drug's most frequent side effects are and, often, how the drug is metabolized and excreted

What kind of volunteers are in Phase 1 of clinical trials?

Majority of the time healthy volunteers

Study purpose of Phase 1 of clinical trials

- is the drug safe?

- what are the effects?

- how does the drug work in the body?

Multiple ascending doses

getting various doses throughout the trial

Phase 1 of clinical trials look at what?

"What a Drug Does to the Body" and "What the Body Does to a Drug"

Typical number of healthy individuals used in Phase 2 of clinical trials

100's of people

What does Phase 2 of clinical trials emphasize?

This phase emphasizes effectiveness

What is the goal of Phase 2 of clinical trials?

To obtain preliminary data on whether the drug works in people who have a certain disease or condition.

Study purpose of Phase 2 of clinical trials

- is the drug safe?

- how effective is the drug?

- how much drug should be taken, how often?

What happens at the end of Phase 2 of clinical trials?

FDA and sponsors discuss how large-scale studies in Phase 3 will be done

What Phase will typically be done in a single center?

Phase 1 or 2

What Phase will typically be done in multiple centers?

Phase 3

Typical number of healthy individuals used in Phase 3 of clinical trials

1,000's of people

What is the goal of Phase 3 of clinical trials?

To gather more information about safety and effectiveness, study different populations and different dosages, and uses the drug in combination with other drugs.

Study purpose of Phase 3 of clinical trials

- is the drug safe?

- how effective is the drug?

- is there a benefit or risk to a specific population?

What Phase has a lot of money being put into it?

Phase 3

NDA

New Drug Application

New Drug application acronym

NDA

BLA

Biologics License Application

Biologics License Application acronym

BLA

Where do Manufacturer submit an NDA or a BLA?

To FDA's Center for Drug Evaluation and Research (CDER)

NDA is used for approval of what?

conventional/chemical drugs

BLA is used for approval of what?

therapeutic biologics

What does CDER do with a NDA/BLA?

1. All human and animal data, including adverse effects that occurred during clinical trials

2. Checks accuracy of information

3. Reviews drug labeling - some labeling is intended for HCPs and some for patients

4. Reviews how drug will be manufactured (and also visits facility)

Phase 4

post-marketing surveillance (drug is on the market)

Objectives of Phase 4 studies

- Study the drug's safety and effectiveness in real life scenarios to study long-term risks and benefits

- Discover any side effects that did not show up in clinical trials

Drug Indication

what the drug is approved for treating

Drug Indication basic structure and required elements

Drug-x is indicated ...

for the treatment, prevention, mitigation, cure, or diagnosis (or relief of symptoms) ...

of a disease or condition (or manifestation thereof) ...

in age group (ex. Adults and pediatric patients Y years and older)

Package Inserts (PIs)

created by the drug's manufacturer and approved as part of the NDA

Approval for new indication

- To gain FDA approval of new uses or indications for an already-approved drug, the manufacturer must submit a Supplemental New Drug Application (sNDA).

- An sNDA establishes the safety and effectiveness of the product for the new use. In some cases, the data required to submit another request may not be as extensive as the one for initial approval.

Approved new indications (through an sNDA) will be added where?

to the drug's package insert

You receive a prescription for PROZAC for a patient with PTSD (post-traumatic stress disorder), but it is not listed as an indication. Is prescriber acting within the law to write for a use that is not an indication?

yes

You receive a prescription for PROZAC for a patient with PTSD (post-traumatic stress disorder), but it is not listed as an indication. Are you acting within the law to fill this prescription?

yes

Off-label drug use

the practice of prescribing a drug for a different purpose than what the FDA approved.

Once a drug has been approved by the FDA for an indication and then marketed for that indication, are physicians are allowed to prescribe the drug for any other indication (treatment for other diseases or conditions)?

Yes if there is reasonable scientific evidence that the drug is effective for that use.

Off-label indications typically are supported by what?

less extensive studies than labeled indications; however, this does not necessarily mean that the drugs are less effective when prescribed for off-label uses than for FDA-approved indications.

Off label use should be based on what?

"based on reasonable medical evidence, done in good faith in the best interests of the patient"

Can off-label uses be used in package inserts?

Nope, they need to go through Clinical testing and approved by FDA

Before 1997, did the FDA require pediatric testing of drugs?

No, they did not do peds dosing

Most drugs for children were prescribed ___/

"off label"

The FDA defines pediatric population as what?

"birth to 16 years, including age groups - neonates, infants, children, and adolescents

Why were pediatric studies not being done during clinical trials?

- financial reason

- need for child-friendly environment - ethical

- there is a concent issue, children cannot give consent, at age 7 they can ascend (say yes or no)

BPCA

Best Pharmaceuticals for Children Act

Best Pharmaceuticals for Children Act

BPCA

PREA

Pediatric Research Equity Act

Which federal law Mandate peds drug studies?

PREA

Which federal law Incentivizes peds drug studies?

BPCA

Best pharmaceuticals for children act (BPCA)

FDA provides a financial incentive to companies who voluntarily conduct pediatric studies for an approved drug upon a written request (or drug company can issue a proposal to FDA). FDA can request pediatric studies for approved uses (indications) and off-label uses (unapproved indications)

Where does the BPCA come into play?

Once the drug is on the market

What is the INCENTIVE for doing this pediatric research?

- If terms of agreement are met, a 6-month exclusivity is given to all existing exclusivities and patents of the drug

- If no exclusivities or patents remain, BPCA facilitates funding for pediatric studies through National Institutes of Health (NIH)

Pediatric research Equity Act (PREA)

FDA requires companies to include a pediatric assessment in their New Drug Application (NDA) or BLA (biologics license application) if the drug is likely to be used in a substantial number of pediatric patients

- The pediatric studies are only for the indication that is the subject of the application

IN the BPCA, the FDA provides a financial incentive to companies who voluntarily conduct pediatric studies for an ___ upon a written request (or drug company can issue a proposal to FDA)

approved drug

In the PREA, the FDA requires companies to include a ___ in their New Drug Application (NDA) or BLA (biologics license application) if the drug is likely to be used in a substantial number of pediatric patients

pediatric assessment

When does the PREA act take place in the drug development timeline?

If it is likely to be used in pediatric population, it must be tested (phase 3) before on the market

A pediatric assessment contains data gathered from pediatric studies to:

- Assess the safety and effectiveness of the drug or the biological product for the claimed indications in all relevant pediatric subpopulations

- Support dosing and administration for each pediatric subpopulation for the claimed indication

PREA Deferral Criteria

- Drug/biologic is ready for approval before completion of pediatric studies

- Pediatric studies should be delayed until more information regarding safety and/or effectiveness is available

PREA Waiver Criteria

- The disease for which the drug is intended to treat is not encountered in the pediatric population

- There is little to no perceived values in children

- The drug may pose an unacceptable risk in children.

When may a drug company apply for a PREA deferral or wavier?

In phase 3 before they submit their NDA

What is the expectation of the drug company if they are granted a PREA deferral?

There is the expectation that the company will do the testing later

FDA's Expedited Approval Program

- Fast track

- Breakthrough therapy

- Accelerated Approval

- Priority Review

Facilitates =

fast track

Expedites =

breakthrough

A drug may start as a fast track but can be moved to what?

breakthrough therapy designation

Fast Track Status

Facilitates the development and expedites review of drugs that are:

- intended to treat a serious condition and,

- preliminary clinical, nonclinical, or predictive evidence indicates that:

- the drug fills an unmet medical need.

Breakthrough Therapy Designation

Expedites 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 available therapy on a clinically significant. endpoint

Serious condition

a disease or condition associated with morbidity that has substantial impact on day-to day functioning (life-threatening diseases or conditions also are considered serious conditions)

Clinically significant endpoint

an endpoint that measures an effect on whether people feel or function better or live longer

Available therapy

a drug approved in the US for the same indication being considered for the new drug

Fast Track Status is the "light" version of what?

Breakthrough Therapy Designation

How fast can Fast track status and Breakthrough Therapy Designation speed up the process?

2-3 years earlier

Benefits of Fast track

- Rolling Review

- NDA or BLA can be submitted in sections for review

- More frequent meetings and communication with FDA related to development plan and design

Benefits of Breakthrough Therapy

- Rolling Review

- NDA or BLA can be submitted in sections for review

- Intensive guidance from FDA for efficient drug development, beginning as early as Phase 1

--- instead of healthy, they are using sick (ex. Chemo to cancer patients)

Fast track drugs are eligible for what?

- Eligible for Accelerated Approval

- Eligible for Priority Review

- May be granted BTT designation

Breakthrough Therapy drugs are eligible for what?

- Eligible for Accelerated Approval

- Eligible for Priority Review

Accelerated Approval

Allows for earlier approval of drugs that are:

- intended to treat a serious condition and,

- fill an unmet medical need

- based on a surrogate endpoint

When does Accelerated approval take place?

Drug gets placed on market before end of trials and submit NDA, however they should still be finishing the trials.

Surrogate endpoint

results used in place of clinical endpoint (ex. a drug shrinks a tumor but it is not known yet if the patient will live longer); surrogate endpoints are typically predictive of clinical benefit

Is accelerated approval full approval?

- Drug companies are required to conduct Phase 4 confirmatory trials to show the drug provides a clinical benefit

- If so, drug is granted traditional approval

- If not, initial approval may be withdrawn from the market

Accelerated Approval real-world example

- Eli Lilly's ALIMTA for lung cancer

- Accelerated Approval Date: June 2018

- Use to treat a form of lung cancer

- Full Approval Date: January 2019

Priority Review Designation

Will direct overall attention and resources to the evaluation of an NDA or BLA for drugs that, if approved, would be significant improvements in the treatment or prevention of serious conditions

Priority Review drugs are reviewed within what time frame?

Within 6 months

Rare Diseases

affect < 200,000 Americans

Orphan Diseases (including rare diseases)

neglected conditions whose treatments are not considered profitable to develop

Examples of orphan diseases

- Lou Gehrig's Disease (ALS)

- Tourette's Syndrome

- Acromegaly