Lecture 3- Drug Development: From Preclinical to Market

Drug Development (Preclinical stage):

• Goal: turn the drug candidate into a product

• Major objectives: 

  • Documentation (records for FDA submission)

  • Determining safety (in vitro and in vivo testing)

  • Confirming biological activity

  • Establishing methods for large -scale manufacture (process chemistry

  • Developing formulation (pill, liquid, patch, spray, etc)

Documentation and patents

• All research is subject to regulatory scrutiny

  • Experiments are tightly regulated

  • Error can have long-term consequences

  • Once a drug reaches the market, any mistake may lead to lawsuits

• All data must be submitted to the FDA

  • Required accurate record keeping and strict lab book disciple

• Patent coverage

  • Protects the drug candidate and all potential and all potential future variations

Patent as intellectual property

• A patent grants the right to exclude others from your invention

• What can be patented: 

  • Processes, machines, manufactured products, and compositions of matter

  • Chemicals:

    • New compounds 

    • Processes for making compounds

    • Methods for using compounds

• What cannot be patented:

  • Laws of nature

  • Physical phenomena

  • Abstract ideas or algorithms

Patent Requirements

• Novelty

  • The invention must be new and not previously disclosed

• Utility

  • It must have a practical application and provide a specific, useful purpose

• Non-obviousness

  • A person “skilled in the art” would not consider the invention as an obvious solution or idea

Process chemistry

• Establish methods for large scale synthesis

  • Reactions often behave differently on a large scale compared to small scale

  • Heat transfer becomes a major challenge

• Limited purification methods

  • Crystalization

  • Distillation

• Process regulated by Good Laboratory Practice (GLP)

  • Strict lab book documentation and compliance required

Company Goals of Process Chemistry

• Optimize synthesis for the lowest cost

  • Cost of goods

  • Energy costs

  • Equipment costs

  • Labor costs

  • Waste disposal costs

  • Safety costs

  • Transportation costs

• Companies often promote these optimizations as environmentally friendly

FDA Requirements for Large-Scale Synthesis

• Reliability 

  • Consistent yield

  • Consistent purity

  • Consistent impurity profile (same impurities in the same proportions each time)

• During development, hundreds of kilograms are typically prepared

Safety Testing I (In-Vitro)

• Extensive biochemical assays

  • Often outsources to contract research organizations

  • Thousands of tests are performed

• Goal: a “clean” safety profile

  • Minimize the number of positive (undesirable) results (<300)

• Identify “deal - breakers” early

  • Carcinogenicity

  • Serious interference with organ function

Safety Testing II (In-vivo)

• Use the smallest animals possible

  • Required less drug

• Use the fewest animals possible 

  • Requires less money

• Testing must involve 2 species (typically one rodent and one non-rodent)

  • Rats - low cost, small size, good reproducibility (genetic uniformity)

  • Dogs - low cost, small size

    • Other animals may be chosen if special circumstance apply

  • Primates - as small as possible, closest similarity to humans

Formulation

• Form of the final product (pill, liquid, patch, etc)

• Active pharmaceutical Ingredient (API)

  • Drug candidate

• Excipients

  • Non-medicinal ingredients

  • Often derived from food industry

  • Combined with the API to create to final product

Common excipients 

• stabilizers:usually, an acid or base, protect from chemical degradation (e.g., oxidation)

• Preservatives: prevent mold of bacterial growth

• Fillers: Ensures consistent dosing (e.g., cellulose, MgSO4)

• Disintegrants: help the pill break apart in the stomach (e.g. starch)

• Binders: Hold ingredients together

• Flavours: Mask unpleasant taste

• Colours: Improve safety and identification

• Lubricants: Facilitate ease of manufacture

Types of Formulation

• Pills or tablets

• Capsules

• Liquids (oral solutions, syrups)

• Topical creams or ointments

• Patches

• Injectable liquids

• Nasal sprays

• Eye drops 

• Suppositories

Investigational New Drug (IND)

• Compounds that successful complete preclinical development become INDs

• An IND application is submitted to the FDA requesting permission to begin clinical trials

• The submission includes extensive data (pharmacology, toxicology, manufacturing, clinical protocols)

• Historically, the paperwork could amount to stacks of documents

Clinical Trials

• Drug tested in humans to assess:

  • Safety 

  • Efficacy

  • Dose range finding

• Requires production of thousand of kilograms of the drug

• Manufacturing must follow Good Manufacturing Practice (GMP) standards

• Clinical trials account for 60-70% of the total cost of developing a new drug

• Conducted in 3 main phases (I,II,II)

 

Double Blind Studies

• Compare 2 groups of patients

  • One group receives the drug

  • The other group receives a placebo

    • Many patients improve just by receiving treatment (placebo effect)

• Placebos are not used for serious illnesses or life threatening conditions

  • Cancer, HIV/AIDS, serious infections, anesthetics

  • In these cases, drugs are compared to existing therapies

• Neither patients nor doctors know the treatment group

  • Prevents bias in reporting and observation

  • Can be difficult to enforce in practice

Nuremberg code (1947)

• Before 1947, there were almost no restrictions on human experimentation

  • No formal code of conduct existed

• The Nuremberg code was created in response to the atrocities committed by Nzai doctors during WWII

• The code established ethical guidelines to:

  • Protect human subjects in research

  • Improve the quality and credibility of experimental results 

Nuremberg code for research on Humans

• Participation must be voluntary

• Informed conceit is required

• Prior animal students should be conducted first

• Benefits must outweigh the risks

• Experiments must be conducted by qualified scientists

• No unnecessary suffering is permitted

• Experiments must be stopped if they become dangerous

• Subjects must be free to withdraw at any time

Government regulation and oversight

• Regulation is essential to ensure the safety and effectiveness of health care

• Covers: drugs, surgical procedures, medical equipment, clinical care

• Extends to animal and human experimentation:

• Major regulatory bodies:

  • FDA(US), Health Canada, EMA (europe)

• Regulation is essential to ensure the safety and effectiveness of health care

• Covers: drugs, surgical procedures, medical equipment, clinical care

• Extends to animal and human experimentation:

• Major regulatory bodies:

  • FDA(US), Health Canada, EMA (europe)

• Small number of healthy participants (<1000)

• Focus on safety only

• Range finding

  • Determine the max tolerated (safe) dose

  • Start near the estimated minimum effective dose from preclinical studies

  • Escalate dose gradually while monitoring safety

• 30% of INDs fail at this stage

• Duration: typically <1 year

Phase II

• Small number of patients (200-300)

• Focus on safety and efficacy 

• Establish the effective dose

• 70% of INDs daily at this stage

• Duration: usually several months to 2 years

Phase III: 

• Large number of patients (thosundas)

• Focus: safety and efficacy

• Detect rare side effects

• 70% of INDs fail at this stage

• Duration: 1-4 years (average)

New Drug Application (NDA)

• fficial application filed with the NDA requesting market approval

• FDA review typically takes 6 months to 1.5 years

• DNA are massive documents containing:

  • Preclinical and clinical trial data

  • Manufacturing and quality control information

  • Labelling and safety information

• Historical perspective:

  • 1990: submission stack was 6 feet high (paper)

  • 2010: required 1-2 semi-trailer of paperwork

  • Now: fully electronic submissions

Market (Post- Approval - Phase IV)

• Companies scale up production (hundreds of tons per year)

• Phase IV - post marketing surveillance

  • Monitor very rare or long term side effects

  • Report adverse events to regulators

• New indications

  • Aim to increase potential markets

• Globally, on average 40-50 new drugs (NMEs and biologics) approved each year

• Small % of marketed drugs may be withdrawn for safety reasons

Orphan drugs

• pharmaceutical agent for rare diseases/conditions

  • Affects free than 200,000 patients in the US

• Currently more than 600 orphan drugs approved

• Smaller clinical trials (since fewer patients are available)

• Incentives for developments

  • 7 years of market exclusivity (US)

  • Tax credits (up to 25% of research costs todays)

  • Waiver of FDA user fees

Government regulation

• Before 1907, drugs were largely unregulated

• Board of Food and Drug Inspection (1907)

  • Focused on labelling only (list of ingredients)

• Food and Drug Administration (1938)

  • Established to ensure the safety of new drugs

  • Passed after the Elixir sulfanilamide tragedy (107 deaths)

Food and Drug Administration (FDA) - 1938

• Ensure the safety of drugs

• Preclinical animal testing was now required (safety only)

• Safety testing in humans

• Clear labelling required: directions for safe use

• ALl testing was done by the companies with FDA review

• FDA inspectors monitored manufacturing quality

Thalidomide

• Developed as a sedative - 1957

  • Very few side effects

• By 1962, thalidomide recognized as a teratogen

  • Phocomelia

  • Nerver marketed in the US

  • Teratogenicity was discovered before DNA approval was given

Teratogen causes birth defects

• From greek work “teratos” meaning “monster”

• Thalidomides was tested in rats

  • Rats do not often give birth to deformed pups

  • In humans, problems with a fetus result in miscarriage, stillbirth or birth defects

Modern safety Standards

• Safety testing must be done in at least 2 animal species

• Typically one rodent (rat) and one non-rodent (monkey)

• Must demonstrate that the drug is bioavailable (gets into the body)

• Testing must use clinically relevant doses

Theory of Teratogenicity for Thalidomide

• Based on animal experiments in 1970s

• Drug was sold as a racemate

  • Vasocontrictor

• Difficult to reproduce the experiment

  • Enantiomer effect required i.p dosing (injection)

  • Racemization of the drug

How the FDA functions

• All testing is done by companies

  • Submit full data to the FDA

  • FDA inspectors check compliance with guidelines

  • Based on this review, FDA approves (or rejects) marketing applications

• FDA required companies to monitor their products post-approval

  • Report any problems(adverse events)

• FDA produces oversight through inspections

  • Ensure manufacturing facilities comply with GMP (good manufacturing practices)

Why industry needs regulation

• Ensures safe products

• Ensures products work as intended

• Provides consumer protection

• Control access to drugs (prevents misuse)

• Increases cost

• May increase taxes

• Can limit or delay access

• Important to balance the almost of regulations

  • Protect consumer

  • Avoid overkill (unnecessary bureaucracy)

    • NDA(1990): stack of 6 feet tall

    • NDA (2010): 1 or 2 semi trailers full of paper

    • Now: electronic