Delivery of Biopharmaceuticals

• Should be addressed during the pre-clinical phase of the drug development process • The route by which the drug candidate is delivered or administered for pre-clinical or clinical trials Bioavailability : proportion of a drug that reaches its site of action after administration Maximum efficacy

• The vast majority of biopharmaceuticals approved are administered by direct injection (or parenterally) : - intravenously (i.v.) - subcutaneously (s.c., directly under the skin) - intramuscularly(i.m., into muscle tissue)

• Parenteral administration: no problem for the drug that are administered infrequently

• Non-parenteral route : frequent administration like insulin more convenient, less invasive, less

painful

• Alternative potential delivery routes : - oral - nasal - transmucosal - transdermal - pulmonary

• Oral delivery system - preferred system due to convenience and patient

compliance - Problems for protein therapeutics : - inactivation due to stomach acid : low pH (3 ~ 3.5) - inactivation due to digestive protease : pepsin, trypsin, chymotrypsin - difficult for the passage across the intestinal mucosa due to relatively large size and hydrophilic nature of proteins - subjected to first-pass metabolism the first organ encountered is the liver significant proportion

of absorbed drugs are removed - bioavailability of biopharmaceuticals < 1 %

• Improvement of bioavailability - physical protection : encapsulation using various polymeric substances like cellulose, polyvinyl alcohol, polymethyacrylates, polystyrene, - formulation as microemulsions/microparticulates - inclusion of protease inhibitors like aprotinin, ovomucoids - permeability enhancers : detergents enhance absorption through the gastrointestinal lining

- Mucoadhesive delivery systems : biopharmaceutical is formulated with/encapsulated in molecules which interact with the intestinal mucosa membranes using lectins or bacterial adhesion proteins

To retain the drug at the absorbing surface for a prolonged period

• Pulmonary delivery - most promising alternative to parenteral delivery systems - macromolecules are adsorbed into the blood via the lung cf) lung is not permeable to solutes of low molecular mass but macromolecules can be absorbed into the blood via the lung - pulmonary adsorption : inversely proportional to a mass of about 500 kDa - bioavailability for therapeutic proteins such as colony-

stimulating factors and interferons: > 50 % compared to s.i.

- High pulmonary bioavailability - very large surface area of the lung - low surface fluid volume, - thin diffusional layer, - relatively slow cell surface clearance - presence of proteolytic inhibitors

• Additional advantages of pulmonary route - the avoidance of first-pass metabolism - the availability of reliable, metered nebulizer-based delivery systems capable of accurate dosage

delivery - no need of penetration enhancers

• Passage through the epithelium and endothelial cellular barriers :

No biopharmaceuticals approved for delivery via pulmonary system to blood stream

• Under research - inhalable dry power insulin formulation by Pfizer and

Aventis under phage III clinical trials: more rapidly absorbed than s.i.

• Nasal, transmucosal, and transdermal delivery systems

- Nasal-based delivery : - easily accessible - high density of blood vessel - large absorption surface area by nasal micovilli

- disadvantages - low bioavailability - clearance of a proportion of administered drug due to mucous blanket - existence of extracellular nasal

proteases/peptidases - low uptake rates for larger (10 kDa) peptides/polypeptides

Pre-clinical trials

• In order to gain approval for therapeutic use, the safety and efficacy of drug candidate should be demonstrated

attained by clinical trials in humans

• Preliminary data, especially safety data : required for clinical trials for human volunteers

• Approval to commence clinical trials is based on pre-clinical pharmacological and toxicological assessment of the potential new drug in animals

- ~ 3 years - $ 10 million ~ $ 30 million - approximately 10 % of potential new drugs survive pre-clinical trials

• The range of major tests during pre-clinical trials : Table 2.4

Pharmacology

• Pharmacology : the study of the properties of drugs and how they interact with/affect the body

• Pharmacokinetics : the fate of a drug in the body ,

particularly its ADME - absorption into the body - distribution within the body - metabolism in the body - excretion from the body - Critical for identifying both any toxic effects and most appropriate method of drug administration - usually undertaken in rats and dogs with respects to

different dosage levels

• Pharmacodynamics :

- the study of the biochemical and physiological effects of drugs on the body, the mechanisms of drug action, side effects, and relationship between drug concentration and effect

- Bioavailability and bioequivalence : assessed in animals as part of pharmacokinetic and/or pharmacodynamic studies

• Toxicity studies

- tests using animal to asses any short-term or long-term toxicity of

potential new drug

- Acute toxicity : assessed by administration of single high dose of

the drug to rodents

- rats and mice (male and female) are usually employed

- LD50 : the quantity of the drug required to cause death of 50 %

of the test animals

requires large quantities of animals lethal dose

• Chronic toxicity studies : - require large numbers of animals - demand daily administration of test drug and clinical

examination - Initial study : to asses drug dosages causing an observable

toxic effect - Main studies at three different dosage levels Highest level : mild toxic effect Lowest level : no effect - Undertaken in two different species : rats and dogs(both male and female) Pathological exam of all animals - The FDA usually recommends a period of ~ 2 years - In Europe, much shorter period

• Reproductive toxicity - Administration of the proposed drug at three different dosage

levels (ranging from non-toxic to slightly toxic) to different groups of the chosen species ( usually rodents)

- Fertility test : to assess the nature of any effect of the drugs on male or female reproductive function - The drug is administered to males for at least 60 days (one full spermatogenesis cycle) - Females are dosed for at least 14 days before they are mated - Evaluation regarding male spermatogenesis, female follicular development, fertilization, implantation and early fetal

development

• Teratogenicity studies

- Teratogen : any substance/agent which can induce fetal developmental abnormalities

- assess whether the drug promotes any developmental abnormality

in the fetus - daily dose of the drug administered to pregnant females (rats and rabbits) - a full autopsy on the mother and fetus

• Mutagenicity tests - chemical-based drugs - asses whether the proposed drug is capable of inducing DNA

damage, either by inducing alterations in chromosomal structure or by promoting changes in nucleotide base sequence

- in vivo and in vitro test using both prokaryotic and eukaryotic organisms

- Ames test : assess the ability of a drug to induce mutation reversions in E coli or Salmonella typhimurium

• Carcinogenicity : - long term test at various dosage levels for rodents for 2 years

• Immunotoxicity : assess the ability of a drug to induce an allergic

or hypersensitive response

• Cell-based assay system - Pre-clinical pharmacological and toxicological

assessment The use of thousands of animals Costly and politically contentious • The use of a whole range of animal and human

cell types

Clinical trials• Approved by an authority on the basis of pre-clinical data for

animals

• Assess the safety and efficacy of any potential new drug in humans with targeted disease : $ 300 ~ 500 million

• The clinical trial process : four consecutive phases

• Phase I trials : emphasis on drug safety in healthy human volunteers

- 20-80 persons, 1 yr - the pharmacological properties (pharmacodynamics and pharmacokinetics) of the drug in humans - the toxicological properties of the drug in humans (establishment of the maximally tolerated dose, MTD) - the appropriate route and frequency of administration of the drug

• Phase II trials : safety and effectiveness in small number of patients who suffer from the condition the drug claims to cure or

alleviate (100~300), 2 years

• Phase III trials : Given the drug proves safe and effective - large scale efficacy and safety testing in 1,000 ~3,000 patients - 3 years - “Safe” generally refers to a favorable risk : benefit ratio the benefits should outweigh any associated risk An appropriate level of efficacy must be defined, ideally prior to

trials because a drug is rarely 100 % effective in all patients - Efficacy could be defined as prevention of death or prolonging of life by a specific time frame Alleviation of disease symptoms or enhancement of the quality of

life

- An acceptable incidence of efficacy : effective in 25 % of all tested patients : If the efficacy is below the minimal acceptable level, clinical trials are terminated• The phase III results largely determine whether or not the

prospective drug subsequently gains approval for general medical use

• On average 10 ~ 20 % of prospective drugs that enter clinical trials are commercialized

• Phase IV : post-marketing safety surveillance over long period of time to assess the long-term safety

- The discovery of long-term unexpected side effects can result in subsequent withdrawal from the market

• Demand for large amount of drug candidate - Preclinical and clinical trials require sufficient quantity

- Suitable production process to be designed prior to pre- clinical and clinical trials

- Scale-up of proposed production process : Initial characterization :~ mg scale Pre-clinical and clinical trials : ~ gram scale Commercial product : 100 g ~ kg scale

- The drug candidate used for preclinical/clinical trials: produced using the same process by which it is intended to undertake final commercial-scale manufacture

- Significant deviation from the production protocol used to generate the materials for trials :

invalidate all the clinical trial results with respect to

the proposed commercialization product - Changes in the final production process might alter the final product characteristics like the active ingredient and contaminant

profile

Clinical trial design

• Usually applied to Phase II and III

• Proper and comprehensive planning of clinical trial : essential to successful development of a drug : Too much complex

A poorly planned and/or executed clinical trials is very costly ( $ 300 ~ 500 million for clinical trials) critical for a successful development of a drug • The first issue when developing a trial protocol : To define

precisely what questions the trials results should be capable of answering

Cf) safety and efficacy (acceptable incidence of efficacy) - effective in 25 % of tested patients)

• Trial size and study population - Clinical trials must have a control group against the test group - The control group : - no intervention - a placebo (i.e., substance such as saline) - the therapy most commonly used at that time to treat the

disease

• The size of the trial is limited by - economic consideration (level of supporting financial resources) - size of population with target disease - size of eligible population willing to participate in the trial

• Smaller trials for phase III would suffice if, - the target disease is very serious/fatal - there are no existing acceptable alternative treatments - the target disease population is quite small - the new drug is clearly effective and exhibits little toxicity

Trial design types

• Choosing proper population : critical to adequate trial design - The specific criteria of patient eligibility should be pre-defined

• A number of trial design types : Table 2.6

• Randomized control studies - most scientifically desirable - Randomly assigning participants into either control or test groups each participant has an equal chance of being assigned to one or other group

- Importance of randomness - removes the potential for bias (conscious or subconscious) - guarantees the validity of subsequent statistical analysis of trial results

- The trial may be blind or unblinded : investigators and participants - double blinded : neither the investigator nor the participants know to which group any individual is assigned - single blind : only the investigator have information - The more blind the trial, the less scope for systematic error introduced by bias Randomized, double blind trial : the most scientifically

pure

- The most significant objection to the randomized control design is an ethical one : if the drug is beneficial, it seems ethically

unsound to deprive up to half the trial participants from receiving the drug

the use of historical control trials : all the trial participants are administered the new drug and the results are compared with previously run trials

the control data are obtained form previously published or unpublished trial results non-randomized and non-concurrent vulnerable to bias

Additional trial design

• Cross-over design trials : randomized control trials - each participant acts as his/her own control each participant receives either a placebo or the test drug for the first half of the trial and receives the alternative

treatment for the second half the order of placebo vs test drug is randomized - Benefit - reduction in variability - use of smaller number of participants

- only used if there is sufficient evidence that there is no carry- over effect from the first-half to the second-half of the trial

• Factorial design : Table 2.7

- used to evaluate the effect of two or more interventions on

participants in a single trial - economically attractive

• Hybrid trial design

- combine of both historical and randomized control studies

- if a substantial amount of control data is available, smaller proportion of the trial participants serve as control. - Majority of participants form the test group

• Typical issues to be addressed when designing a clinical trial protocol : Table 2.8

The role and remit of regulatory authority

• The pharmaceutical industry : one of the most highly regulated industries

• All regulations : to ensure that every aspect of pharmaceutical activity is tightly controlled

• The Food and Drug Administration (FDA) in the US - Founded in 1927 to protect “ public health” : regulates

many drugs /consumer items $ 1 trillion value - Foods, drugs, blood supply and products, medical devices, cosmetics, microwave oven, advertising promotional claims - Total annual budget : $ 1 billion, 9,000 people - Organization of FDA (Fig. 2.10) - Biopharmaceutical drug approval/regulation by Center for Drug Evaluation and Research (CDER) and the Center for Biologics Evaluation and Research (CBER)

The major FDA responsibility

• To assess pre-clinical data, and decide whether a potential drug is safe enough to allow clinical trials

• To protect the interests and rights of patients participating in clinical trials

• • To asses pre-clinical and clinical trial data, and decide

whether a potential drug should be made available for general medical use

( i.e., whether it should be granted a marketing license)

• To oversee the manufacture of safe and effective drugs - inspect and approve drug manufacturing facilities on the basis of compliance of cGMP as applied to pharmaceuticals • To ensure the safety of the US blood supply

• CDER : regulates the development and marketing approval of

mainly chemical-based drugs• CBER : Biopharmaceutical products • The criteria used by CBER and CDER in assessing drugs

during the development process : safety, efficacy, and quality

Investigational new drug (IND) application

• Investigational New Drug (IND) : A new chemical-based, biologic or biopharmaceuticals for which the FDA has given approval to undergo clinical trials

• IND application : detailed information on pre-clinical trials, method of product manufacture, and proposed protocol for initial clinical trials

- An IND application consists of up to 15 volume of approximately 400 pages each

• The major itemized points that should be included/addressed in an IND application : Table 2. 12

• Detailed review of the submitted dossier• Make a decision on approval to undergo clinical trials • IND application process : Figure 2.11

The new drug application(NDA)

• On completion of clinical trials for CDER-related drugs, the documents are submitted to FDA to get approval to produce and market : New Drug Application

• The NDA consists of 200-300 volumes, representing a total of over 120,000 pages

• The contents of a typical NDA : Table 2.13

• The review process for submitted NDA (Fig. 2. 12) - Preliminary inspection of document for filing - Once filed, an NDA undergoes several layers of review by a

panel - Primary review - Secondary review - Review and recommendation - Entire process : ~ 12 months