Drug Development and Regulation

Unit 5: Drug Development and Regulation

Objectives

• Understand the basic principles of pharmacology.
• Discuss the pharmacokinetics and pharmacodynamic actions of drugs.

Drug Discovery

• Approaches to discovering and developing new drugs:
  1. Random Screening
  2. Chemical Modification of a Known Active Molecule
  3. Identification or Elucidation of a New Drug Target
  4. Rational Drug Designing

1) Random Screening

• Screening for biologic activity of large numbers of natural products, previously discovered chemical entities, or large libraries of peptides, nucleic acids, and other organic molecules.
• Commonly employed by extracting an active constituent from a natural source (e.g., plant, animal) and testing for therapeutic activity.
  • Example: Using banana peels for antifungal treatment or squid ink as soap.

2) Chemical Modification of a Known Active Molecule

• Creating a “me-too” analog by chemically modifying a known active molecule.

3) Identification or Elucidation of a New Drug Target

4) Rational Drug Designing

• Designing a new molecule based on understanding biologic mechanisms and drug receptor structure.
• Requires making a drug design to enable the pharmaceutical product to cross into the cell and bond to a receptor to produce an effect.

Drug Screening

• Assays at molecular, cellular, organ system, and whole animal levels to define the pharmacologic profile:
  • Drug Activity
  • Drug Selectivity
• Testing in research animals to determine drug activity and selectivity.

Drug Screening Assay

1. Molecular Level
   • Screening the compound for activity on the target.
   • Testing the potential drug in a cell or homologous animal receptor to find out its affinity.
   • Example: Receptor binding affinity to cell membranes containing the homologous animal receptors.
2. Cellular Level
   • Determining whether the drug is an agonist (activates receptor), partial agonist, inverse agonist, or antagonist (blocks receptor) at relevant receptors.
   • What would be its effect into the cell.
3. Whole Animal Level
   • Determining the effect of the drug on:
     • organ system models
     • disease models
   • The desired result is a lead compound, which is the leading candidate for a successful new drug.

Rough Estimate of Length of Drug Creation

• (1) In vitro studies: 0-2 years
• (2) Animal testing: 2-4 years
• (3) Clinical testing: 4-8/9 years
• (4) Marketing: 9-20 years
• In vitro studies involve testing in models or test tubes.
• After in vitro studies, the lead compound goes to animal testing.

Preclinical Safety and Toxicity Testing

• "All chemicals are toxic in some individuals at some dose."
• Evaluation for potential risks before and during clinical testing.
  • Identifying potential human toxicities.
  • Designing tests to further define the toxic mechanisms.
  • Predicting the most relevant toxicities to be monitored in clinical trials.
• Testing on animals before application to human beings.

Limitations of Preclinical Testing:

1. Toxicity testing is time-consuming and expensive (2-6 years).
2. Large numbers of animals may be needed to obtain valid preclinical data.
   • Cell and tissue culture in vitro methods and computer modeling are increasingly being used, but their predictive value is still limited compared to preclinical testing in animals.
3. Extrapolations of toxicity data from animals to humans are reasonably predictive for many but not for all toxicities.
   • Sometimes, toxicities are not discovered in animal studies but are seen in clinical trials.
4. Statistically, rare adverse effects are unlikely to be detected in preclinical testing.
5. Animal testing can take up to 2 years on average.
6. The goal of animal testing is to look at the efficacy of the lead compound, its selectivity, and its mechanisms of action.
7. After animal testing, an application for Investigational New Drug (IND) can be submitted to the FDA.
   • By this time, the lead compound will become an IND and it is first applied in FDA.

Evaluation in Humans

Confounding Factors in Clinical Trials

1. Most Diseases Have Variable Natural History
2. The Presence of Other Diseases and Risk Factors
3. Subject and Observer Bias and Other Factors

1) Most Diseases Have Variable Natural History

• Natural history of disease, according to CDC, refers to the progression of the disease process in an individual over time in the absence of treatment.
• Diseases may vary, evolve, or mutate, especially if left untreated.
  • Prevention: Evaluating a large enough population of subjects over a sufficient period of time.
  • Use of a crossover design, which consists of alternating periods of administration of test drug, placebo preparation (the control), and the standard treatment (positive control), if any, in each subject.

2) The Presence of Other Diseases and Risk Factors

• Prevention:
  • Crossover technique (when feasible).
  • Proper selection and assignment of patients to each of the study groups.
  • Statistically valid methods of Randomization in assigning subjects to particular study groups.
• Inclusion and exclusion criteria in research.
  • Example: Testing a drug for hypertension (HTN) requires only people with hypertension.
    • Inclusion criteria: only people with hypertension, without kidney disease

3) Subject and Observer Bias and Other Factors

• Prevention:
  • Single-blind design – reduces subject bias; participants do not know what group they belong to or what treatment they are receiving
  • Double-blind design – reduces observer bias; neither the observer (or doctor) nor the subject knows the grouping, only the drug sponsor or drug manufacturer
  • Adherence - confirmation of compliance with protocols; observers need to follow the protocols in doing the research.

The Philippine FDA

• Republic Act No. 9711, “The Food and Drug Administration Act of 2009”
• Responsible for licensing, monitoring, and regulation of:
  • cosmetics
  • drugs
  • foods
  • household hazardous products
  • medical devices and electromagnetic radiation emitting devices
  • pesticides
  • tobacco and related products
  • vaccines for safety, efficacy, and quality
• To undergo clinical trial, an application for IND must be submitted to the Philippine FDA to be granted a license or a certificate of product registration.
• Without product registration, the product cannot be marketed in the Philippines.

Clinical Trials: The IND & NDA

Investigational New Drug (IND)

• A Notice of IND must be filed with the FDA once a new drug is judged ready to be studied in humans.
• Chronic safety testing in animals is usually done concurrently with clinical trials.

Phases of Clinical Trials:

PHASE I

• Effects of the drug as a function of dosage (safe clinical dosage range)
• Small number (20–100) of healthy volunteers (people who do not have the disease)
• Pharmacokinetic measurements (ADME studies) are also being done
• Either “open” or “blinded” trials
  • Open: the patient knows what he or she is receiving
  • Blinded: the patient is not aware of what drug he or she is taking

PHASE II

• Modest number (100-200) of patients with the target disease to determine its efficacy (“proof of concept”).
• Determine if the drug really treats the target disease in a human being.
• Single-blind design is used in phase II.
• A broader range of toxicities may be detected.
• Has the highest rate of drug failures; only 25% of innovative drugs move on to phase 3.

PHASE III

• Done to minimize errors caused by placebo effects, variable course of the disease, and other factors.
• Tested on a large number (1000-6000) of patients to further establish and confirm safety and efficacy.
• Double-blind and crossover techniques are employed.
• Difficult to design and execute, and are usually expensive because a large population group and more observers are needed.
• The drug is formulated as intended for the market.
• If the drug passes in all the phases of the clinical trials, the drug sponsor or manufacturer will now apply for a New Drug Application (NDA).

New Drug Application (NDA)

• If Phase 3 results meet expectations, an application is made for permission to market the new agent.
• FDA review leading to approval (or denial) of the new drug application may vary from months to years.
• Once approval to market a drug has been obtained, phase 4 begins.

PHASE IV (Postmarketing Surveillance)

• Low incidence drug effects are not generally detected before phase 4 no matter how carefully phase 1, 2, and 3 studies are executed.
• Phase IV has no fixed duration.
• As with monitoring of drugs granted accelerated approval, phase 4 monitoring has often been lax.
  • Example: COVID-19 vaccines

Drug Patent

• The time from the filing of a patent application to approval for marketing of a new drug may be 5 years or considerably longer.
• Lifetime of a patent is 20 years in the USA & PH.

Orphan Drugs & Treatment of Rare Diseases

• Drugs for rare diseases are called orphan drugs.
• It can be difficult to research, develop, and market.
• Proof of drug safety and efficacy in small populations must be established.
  • The disease is probably one in a million. Only a few people get this condition, which is why not a lot of companies will invest money in this.
• Funded by NGO’s & NPO’s.