The Industry-Academic-Regulatory Axis (L9; E3)

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Questions and Answers

What is the approximate percentage of FDA approval rates for oncology drugs?

15%

10%

8% (correct)

20%

Which phase of drug development is considered the most expensive?

Phase 3 (correct)

Phase 1

Registration

Phase 2

How many new oncology drugs entered clinical trials between 2002 and 2005?

~250

~325 (correct)

~400

~150

What is the median time for clinical trials of oncology drugs?

7.8 years Signup and view all the answers

What percentage of phase 2 drugs are successful enough to proceed to phase 3?

30% Signup and view all the answers

What is the primary purpose of the Investigational New Drug application (IND)?

To compile preclinical development history and proposed clinical plans Signup and view all the answers

Which agency is primarily responsible for regulating drug testing in humans in the United States?

Food and Drug Administration (FDA) Signup and view all the answers

What occurs after sufficient testing of a new drug has been completed?

A New Drug Application is submitted to the FDA Signup and view all the answers

How often must an active Investigational New Drug application (IND) be updated?

Annually Signup and view all the answers

Which of the following is NOT a regulatory authority in drug evaluation?

American Medical Association (AMA) Signup and view all the answers

What are the two key responsibilities of the FDA in drug development?

Regulatory review and oversight Signup and view all the answers

What typically initiates the complex drug approval process in the US?

Completion of promising preclinical results Signup and view all the answers

What did the Kefauver-Harris Amendments require regarding drug approval?

Drugs must be shown scientifically to be effective. Signup and view all the answers

Which of the following was NOT a limitation in drug development between 1960 and 1985?

Extensive data on drug-drug interactions. Signup and view all the answers

What was a significant outcome of the Orphan Drug Act of 1983?

It provided benefits for the research of drugs for rare diseases. Signup and view all the answers

What was a major reform introduced by the FDA Modernization Act of 1997?

It allowed for electronic submissions and reduced review times. Signup and view all the answers

What is the primary focus of comparative premarket trials in drug development?

Demonstration of noninferiority compared to a single control drug Signup and view all the answers

How long does the FDA usually evaluate an IND submission?

30 days. Signup and view all the answers

What factor significantly contributes to the rising costs of developing new drugs?

High rates of clinical trial failures Signup and view all the answers

Which of the following phases does NOT pertain to regulatory drug development?

Prescription approval phase. Signup and view all the answers

What is the standard review timeline for an NDA submission?

10 months. Signup and view all the answers

Which of the following represents a significant concern regarding phase 3 trials?

High percentage of late-stage clinical failures Signup and view all the answers

What is a potential consequence of rapid market uptake of new drugs?

Exposure of many individuals to drug problems before identification Signup and view all the answers

Which of the following is true regarding the FDA's requirements from the 1980s to the 1990s?

The FDA expanded requirements to include more data during drug development. Signup and view all the answers

What dual role does the FDA play in drug development?

Ensuring benefits outweigh risks while promoting health innovations Signup and view all the answers

What was a primary focus of the Best Pharmaceuticals for Children Act of 2001?

To create an office within the FDA for pediatric therapeutics. Signup and view all the answers

What effect does the high cost of drug development have on pharmaceutical innovation?

It discourages risky approaches and treatments for smaller markets Signup and view all the answers

In which year did the development of new chemical entities reach a 20-year low?

2004 Signup and view all the answers

What is one reason for the increasing investment needed for successful new drug development?

The increasing numbers of clinical failure rates Signup and view all the answers

Which aspect of public health was emphasized due to rising social demands during the early 2000s?

Increased certainty of outcomes from drug therapies Signup and view all the answers

What was a significant outcome of the Critical Path Initiative launched in 2004?

It identified the importance of public-private partnerships. Signup and view all the answers

How did drug development trends from 1994 to 2004 affect pharmaceutical spending?

Spending increased significantly despite a decrease in drug development. Signup and view all the answers

Which technological advancements were intended to be incorporated into the Critical Path process?

Genomics and advanced imaging technologies. Signup and view all the answers

What did the FDA's 2004 White Paper highlight as an issue in drug development?

The lagging science of drug development. Signup and view all the answers

What trend was observed in the approval of new molecular entities (NMEs) in oncology during 2018?

There was a significant increase in NMEs approved for orphan drugs. Signup and view all the answers

What change was observed in the review of oncology drug applications?

There was an increase in both standard and priority reviews. Signup and view all the answers

Which statement best describes the 'Critical Path' as identified by the Critical Path Initiative?

It encompasses all phases of drug marketing and evaluation. Signup and view all the answers

What does the increase in targeted therapies imply for the pharmaceutical market?

An increase in the number of new molecular entities entering the market. Signup and view all the answers

What was a notable trend in drug development from 2000 to 2004?

It faced high levels of investment but low new approvals. Signup and view all the answers

What did the FDA's recognition of the 'Critical Path' signify?

A strategic approach to modernize and improve drug development. Signup and view all the answers

Study Notes

Oncology Drug Discovery & Development: The Industry-Academic-Regulatory Axis

Oncology drug development is a complex process, involving academic institutions, the pharmaceutical industry, and government agencies.
Significant funding for primary and clinical research is provided by the National Institutes of Health (NIH).
The Food and Drug Administration (FDA) oversees and regulates the drug development process.
The Investigational New Drug (IND) application is the primary mechanism the FDA uses to control human clinical trials.
A New Drug Application (NDA) summarizes all data necessary for risk/benefit analysis and is submitted to the FDA for review and approval after sufficient testing.
Understanding the regulatory process and NIH funding is essential for researchers involved in clinical trials.

The Drug Approval Process

New drug development is a complex, highly regulated process.
Academic institutions, pharmaceutical companies and government agencies have roles in the process.
The FDA regulates preclinical and clinical trials.
The IND is the initial application submitted by sponsors to the FDA.
Clinical trials move through phases 1-3 to gather information on safety and effectiveness.
The NDA summarizes data for the FDA review of the new drug; this typically includes: animal pharmacology, toxicology, chemistry, manufacturing, human pharmacokinetics, bioavailability, and pharmacology, pharmacodynamics and clinical efficacy and safety.
A priority rating is assigned to each application, 'S' for similar drugs, 'P' for new treatments.
The FDA must approve the drug before it can be marketed.

Regulatory Health Authorities

USA: FDA - Food and Drug Administration
CDER: Center for Drug Evaluation and Research
CBER: Center for Biologics Evaluation and Research
Europe: EMEA - European Medicines Agency
CHMP: Committee for Human Medicinal Products
Japan: Ministry of Health, Labor and Welfare (MHLW), Pharmaceuticals and Medical Devices Agency (PMDA)
Canada: Health Canada, Therapeutic Products Directorate (TPD)

Drug Approval Process (Continued)

A promising drug profile, combined with clinical development plans, is included in the IND application submitted to the FDA.
Active INDs are documents for ongoing clinical research in humans, updated annually by the sponsor.
INDs should include data and information on animal pharmacology testing, toxicology, safety parameters, manufacturing details to guarantee consistent batches, and clinical protocol and information ensuring no unnecessary risk to patients and qualified researchers.
Clinical trials (phases 1-3) assess safety, efficacy, and dosage regimens.
A comprehensive NDA summarizes all relevant data on the drug, including chemistry, manufacturing, preclinical pharmacology and toxicology, pharmacokinetics, bioavailability, and clinical efficacy and safety.
The FDA assigns a letter code signifying the review priority, 'S', for similar drugs or 'P', for new, innovative medications.
Drugs are marketed only after the FDA approves them, signing an approval letter.

Drug Approval Process (Continued Phase Study Characteristics)

Phase 1: Initial human testing; focus on safety and dosage; small number of healthy volunteers (20-80 patients)
Phase 2: Establish the proof of concept, efficacy, and dosing strategies in patients with the specific disease or condition (usually healthy volunteers).
Phase 3: Confirm safety and efficacy; involve hundreds, or thousands, of patients and last for months or years; FDA requires 2 well-controlled studies.
Phase 4: Post-marketing studies for long-term safety and efficacy assessment; includes analysis of various pharmacoeconomic outcomes.

Additional Laws Pertaining to Drug Therapy

Orphan Drug Act (1983): Incentives for research, development, and approval of medicines for rare diseases.
Prescription Drug User Fee Act (1992): Established user fees for applications and expedited the FDA approval process.
FDA Modernization Act (1997): Reduced review times and allowed for electronic submissions.
Best Pharmaceuticals for Children Act (2001): Created a specific FDA office focused on pediatric therapeutics.

The 3 Phases of Regulatory Development

IND submissions are evaluated in 30 days.
If no issues are found, trials begin, under FDA oversight.
NDA review, typically 6-10 months (flexible), considers approval, conditional approval, or rejection.
Important documents include package inserts for prescribing information.
The FDA Office of Drug Safety oversees post-marketing safety.

Improvements in FDA Regulations

Fast Track (FDAMA 1997): Addresses medical need before a drug is on the market
Priority Review (PDUFA 1992): Review process reduced from 10 to 6 months, focusing on 'unmet' medical needs.
Accelerated Approval (1992): Approves drugs for serious or life-threatening illnesses if they demonstrate a meaningful therapeutic benefit; allows for surrogate endpoints.

Accelerated Approval (Oncology)

Accelerated approval (AA) for oncology drugs (1992) is a method to introduce new medicines to patients with life-threatening illnesses rapidly.
Once AA is approved, sponsors must conduct Phase 3 to definitively confirm effectiveness.
In 2003/2005, the Oncologic Drugs Advisory Committee provided guidance (ODAC) to prioritize critical trials for cancer patients.
Conducting these Phase 3 clinical trials for oncology drugs is challenging because these patients frequently contain a small number of patients.

Oncology vs. Other Drugs (FDA Process)

Data suggests oncology drugs frequently receive priority review and expedited approvals based on their significant or unmet medical need.

Challenges to Progress in Drug Development

Long-term drug use data is limited.
Technologies to detect rare, catastrophic side effects are lacking.
Patients enrolled in clinical trials don't always represent the full diversity of the patient population experiencing the illness.
New safety issues are often identified only upon drug entry into the market.
The drug development process is complex and costly.
A multitude of drug options exists (making design of the trials more complicated).

Challenges to Drug Development in the 2000s (cont.)

A decline in the successful development and launch of new drugs (~2004, 20-yr low) due to difficulties in ensuring efficacy.
Increasing cost of creating successful drugs (~$800 Million to $2 Billion+) due to high rate of clinical failure (upwards of 70%-90%).
Costs related to late-phase drug development (~50% of compounds are failing clinical trials), deter new investments.
Existing needs for recouping investments in exclusivity precede the introduction of generic copies that drive marketing strategies.

Challenges to Progress in Drug Development in Early 2000s (cont.)

Public health concerns and demands for greater certainty in drug outcomes coincided with industry difficulties in sustaining innovation.
FDA's role includes policies to ensure the benefits of new drug products outweigh risks and promoting innovation.
A need for strategies to improve and modernize drug development efficiency.
The "Critical Path Initiative" highlighted the need for a focused, improved process for drug development.

Biological Therapies

Biological therapies are treatments derived from natural or endogenous compounds in the body; used as defense mechanisms and part of naturally occurring biochemical processes.
This includes but it is not limited to: Protein/Peptide Therapeutics, Monoclonal Antibodies, Aptamers and Antibody Derivatives, Oligonucleotides, RNA. Gene Therapy, Cell Therapy, Immunotherapy

Drug Development process (Timeline)

A diagram illustrates the drug development timeline, showing the progression from basic research to final product launch and post-launch monitoring.

Types of Drug Targets

Drug targets are typically proteins, although nucleic acids can also be targets.

Pharmaceutical Development Process

A figure illustrates the stages of the pharmaceutical development process, from the lead compound to establishment of the final molecule.

Discovery, Preclinical, Phase I, Phase II, Phase III, NDA/BLA, approval, market

The Cost of Drugs Development (Statistics)

Data on the cost of drug development vary.
Costs are generally increasing.
Correlation between number of approved drugs and decrease in the proportion spent in the R&D phase.
Newer genomic and proteomic technologies have varying impacts.

Stages of Pharmaceutical R&D

A breakdown of stages in drug development, including timeframes and probabilities to obtain licensure.
Stages include: Discovery and preclinical, Phase I, Phase II, Phase III, Licensure, and Production.

Medical Device Approaches

Non-pharmacological cancer therapies (e.g., Radiotherapy), combining therapies.
Interventional approaches (e.g., surgical tools).

Perspectives

Scientific breakthroughs provide life-saving treatments (like imatinib, Trastuzumab).
Industry-academia-government collaboration is crucial.
Future need for scientists, clinicians, and healthcare workers is highlighted.

The Market: Understanding the Customer

Begin market research early and continuously.
Segment and target the customer base.
Position the product effectively to meet their specific needs.
Recognize that not all products appeal to all customers.

Profit/Loss Statement

Revenue.
Cost of goods sold (COGS).
Selling, general and administrative expenses (SG&A), particularly Marketing and Sales expenses.
Research and Development (R&D) expenses.
Interest expenses.
Taxes.
Net Income.

Earnings After Approval

Pharmaceutical companies have considerable returns for some time after a drug's approval, declining eventually due to generics.

Intellectual Property (IP)

Protection of innovations through measures such as: Trademarks, Copyrights, Trade Secrets, Patents, Patent Term Restoration provision or Data Exclusivity or Orphan / Pediatric Exclusivity

Effects of Short Patent Lives on Safety

Drug development is multifaceted and prolonged.
New chemical entities (NCEs) are identified, studied and synthesized, and are typically high in quantity (on average) before identification of a suitable treatment.
Post-approval marketing leads to wide use of developed treatments, and patients will benefit.
Patents are typically limited to 20 years, limiting the time to recoup development costs.
Unexpected effects in humans may only manifest after sufficient patient exposure.

Unexpected Adverse Drug Reactions (ADRs)

The current systems for reporting are limited and fail to capture a large percentage of discovered adverse drug events (ADRs), which may occur years after regulatory approval.
This is due in part to limited patient exposure in trials.
There are calls to increase the patent period to cover additional clinical trials, for a fuller understanding of possible long-term effects and patient exposure.

Generics

Generics are aggressivly challenging existing patents and providing low-cost drug options.
Biogenerics have been common practice in the EU, and are expected to become more prevalent in the US.

Change in Drug Prices with Increased Generics

Increase in competing drug manufacturers and generic availability correlative with reductions in the price of the medication.

Worldwide Total Prescription Drug Sales

Worldwide drug prescriptions (excluding generics and orphan drugs) have been steadily increasing.

Important Considerations for the Pharmaceutical Industry

A diverse group of participants involved in the industry-academia-government axis is necessary for the production of successful drugs.

Industry Collaborative Groups

Institutions (over 1700) participate in industry-funded or cooperative research and trials (particularly in oncology).
This involves conducting preclinical, phase-2, phase-3, and post-marketing trials.

Level of Evidence: Types of Studies

There is a hierarchical structure to evidence; beginning with meta-analysis evidence (strongest) at the top of a triangle to retrospective anecdotal evidence (weakest) at the bottom of the triangle.
Studies such as phase 3, randomized clinical trials are considered the gold standard (level 1) for clinical evidence.

Improvements To Pharmaceutical R&D

Various strategies to improve efficiencies include phase 1 ext., adaptive strategies and specialized trials.

Utilizing Emerging Technology

Genomics, Proteomics, Metabolomics, Imaging technologies.
Targeted therapy, Immune checkpoint inhibitors, "Designer Drugs" and cell therapy are emerging areas.
Personalized medicine has become more common.

External Innovation

Methods include licensing deals, mergers, acquisitions, and scientific collaborations.

Medical Device and Interventional Approaches

Focus on radiotherapy and emerging interventional techniques in cancer treatment.

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Description

Test your knowledge on the drug development process for oncology drugs, including FDA approval rates and phases of development. This quiz covers key regulatory aspects and statistics related to clinical trials and drug applications in the United States.