DRUG DEVELOPMENT. the roots of Western medicine lie in Ancient Greece: disease and healing were seen in a supernatural context –Healing and religion.

DRUG DEVELOPMENT

• the roots of Western medicine lie in Ancient Greece: disease and healing were seen in a supernatural context– Healing and religion went hand-in-hand.

Illness was often seen as divine punishment.

• ill health came from an imbalance between the four “humours”: blood, phlegm, yellow bile and black bile

• the Romans began to use plants as a source of healing

• it wasn’t until the 14th century that medicine became a “study”

• in the 19th century apothecaries started up: pharmacies!

• germ theory of disease came about at the end of the 19th century (Pasteur)

• chemists began to explore how microbes could be killed…pharmaceutical industry was about to be born

• after WWII pharmaceutical companies led a therapeutic revolution

BUT…

• bacteria developed resistance• doctors were accused of prescribing medications

without looking at patients’ well-being• pharma industry became VERY lucrative:

– US$600 billion spent in 2006 on prescription pharmaceuticals

Pharmaceutical company

• Large company researching and making new drugs (collectively often called ‘pharma’).

• Invest a lot of money into marketing the medications directly to doctors and lobbying politicians…

Making a Drug

• A loooooooong and VERY costly process

1. A team of scientists gets the idea for a potential therapeutic.

2. They apply for funding, do some more tests, and patent the technology.

3. Further research outside academia is done to sort out the exact mechanism of the chemical’s action.

5. The extensive research required to conduct animal trials requires more funding – a pharmaceutical company gets involved.– Animal trials: wide dose range to establish toxicity and efficacy

– Phase I trials: 20 – 100 healthy volunteers test the drug to see safety/tolerability/efficacy in humans

– Phase II trials: randomized clinical trials (20-300 volunteers) for safety and efficacy (this can take years to see effects: ex. cancer drugs)

– Phase III trials: multicentre trials (300 -3000 volunteers)

5. License the medication

• government approval for release to market (different countries have different regulatory requirements)

• health care funding? will the drug be covered under provincial plans?

• ongoing (Phase IV) monitoring for side effects

• Costs vary widely and are incurred over several years:

– manufacturing the drug(s)/device(s) tested

– staff salaries for the designers and administrators of the trial

– payments to the contract research organization, the site

– management organization (if used) and any outside consultants

– payments to local researchers (and their staffs) for their time and effort in recruiting patients and collecting data for the sponsor

– study materials and shipping

– communication with the local researchers, including onsite monitoring by the CRO before and (in some cases) multiple times during the study

– one or more investigator training meetings

– costs incurred by the local researchers such as pharmacy fees

– any payments to patients enrolled in the trial

• “Many drugs that are assumed to be effective are probably little better than placebos, but there is no way to know because negative results are hidden.... Because favorable results were published and unfavorable results buried ... the public and the medical profession believed these drugs were potent.... Clinical trials are also biased through designs for research that are chosen to yield favorable results for sponsors. For example, the sponsor's drug may be compared with another drug administered at a dose so low that the sponsor's drug looks more powerful. Or a drug that is likely to be used by older people will be tested in young people, so that side effects are less likely to emerge. A common form of bias stems from the standard practice of comparing a new drug with a placebo, when the relevant question is how it compares with an existing drug. In short, it is often possible to make clinical trials come out pretty much any way you want, which is why it's so important that investigators be truly disinterested in the outcome of their work.... It is simply no longer possible to believe much of the clinical research that is published, or to rely on the judgment of trusted physicians or authoritative medical guidelines. I take no pleasure in this conclusion, which I reached slowly and reluctantly over my two decades as an editor of the New England Journal of Medicine.[34]”

- Marcia Angell, 2009

Some ongoing issues with drug trials…

• members of medical school faculties who conduct clinical trials can receive payments from drug companies beyond research support

• research support often comes with “strings attached”: the researcher needs the company’s approval to publish findings

• relatively easy to abuse (ex. suppress negative findings, “seeding trials”)

What drug do:

• most are small organic molecules (big guys tend to denature, ex. proteins)

• they latch onto cells/proteins, changing their function– inhibit/activate a

biochemical pathway

Safety & Trials

• drug trials are not without risk to volunteers

• drugs already on the market are not without risk

ex. Thalidomide, over-the-counter drug for morning sickness (1950’s: 8000-12 000 children affected)

ex. Vioxx, a painkiller (2004: estimated to have caused 88 000–139 000 heart attacks,30–40 per cent of them fatal)

The future of pharma: Individualized Medicine

• pharmacogenetics: – tailoring drugs to your genetics