07 Sep From molecule to medicine cabinet: how our drugs are made

Issued by IPASA

We’ve become accustomed to taking medicines: you get sick, see your doctor, get a prescription and your friendly pharmacist gives you the drugs you need. But few people consider what it takes for those medications to arrive on the shelf – on average it’s a 15-year process from conception to distribution.

Dries Oelofse, business development manager at H3D, an integrated drug discovery and development centre at the University of Cape Town, points out that, traditionally, Western medicine began with the discovery of natural products that had medicinal properties. These would be ground up or refined in some way, and then converted into medication.

“There is still work in that area,” he says. “For example, Table Mountain has more plant varieties than all of the UK, so the hypothesis is that there must be useful chemicals in those plants, including possible medicines.”

The other option, he adds, is to employ human ingenuity instead of nature – by creating large collections of synthetic molecules and screening them to see if any have the potential to become medicines.

“Drugs have to fulfil two very important functions,” says Dr Konji Sebati, CEO of the Innovative Pharmaceutical Association South Africa (Ipasa). “They have to be safe and they have to work. That requires extensive testing, and the process is strictly regulated.”

Briefly, the process followed to develop drugs is as follows:

1. Create a molecule library: Generate large libraries of small molecules (hundreds of thousands) that can be screened to determine whether they can become drugs. “Pharmaceutical companies will have huge libraries of these molecules, which is where a large part of the value of the company sits. It’s a corporate asset where their blockbuster drugs can come from,” says Oelofse.
2. Set up assays: Assays are initial tests that screen the library until you get a “hit” – a molecule that verifiably kills malaria, for example. The molecule is still just a basic shape at this stage, and the question is just whether in its fundamental form it kills any kind of diseased cell or pathogen.
3. Hit to lead phase: At this stage, researchers start to chemically alter the molecule and optimise its qualities. “Bear in mind that, for example, a pill has to go into your digestive tract and be released to get into your bloodstream,” says Oelofse. Each change that is made to the molecule could decrease its safety and/or efficacy. After all the editing of the molecule, typically there are a few permutations of the same molecule available for further testing.
4. Lead optimisation: Various permutations of the lead candidate series are tested further. Problematic ones are ruled out until one option remains – a possible new medicine. This option is subjected to rigorous and expensive tests, including for possible neurological side-effects, until the researchers have what they call a lead candidate. This can take up to six years on average and is truly a rare occurrence.
5. Lead candidate: This is a molecule the researchers believe will do something specific (like kill the malaria parasite) in a new way without harming the patient in any way.
6. Pre-clinical development: Regulations require that drugs first be tested on animal models, according to strict ethical guidelines. “It’s uncomfortable, but the alternative is to give it to people when you’re not sure it’s safe,” says Oelofse, “and sick people at that.” At this stage, researchers must gather enough data to show that it is safe and get regulatory approval for clinical trials.
7. Phase-one clinical development: Healthy volunteers in small groups are given predicted doses and are constantly monitored by doctors. They spend a defined period in a hospital setting where researchers can check them closely, constantly monitoring for safety and using the data generated to determine dosage for later clinical trials.
8. Phase-two clinical development: This is a pivotal part in the development of a new drug, where the molecule is given to sick people for the first time. Oelofse says that if a drug maker can prove at this point that it’s safe, efficacious and complimentary and/or different from anything else on the market, then it has mitigated a large part of the risk associated with bringing a new medicine to market and can take it forward to a large clinical trial.
9. Phase-three clinical development: These are big studies with potentially thousands of patients. The idea is to generate enough data to prove that the drug is safe and that it works in a large population as well as being better than or different from what’s already on the market to solve the same problem.
10. Approval to launch: The drug is submitted to regulatory authorities for approval, which can take up to 5 years. Once that is received, only then does the manufacturing, distribution and sale of the new medicine can start.

Oelofse points out that the industry average in terms of development costs for a new drug is about $1-billion, including failures, and the process typically takes up to 15 years.

“It’s a risky business, but medicines save lives, improve health and prolong and enhance the quality of life,” says Sebati. “Medicines also reduce overall healthcare costs by speeding up recovery times, and often reduce the need for surgery and hospitalisation”. She continues to say “but many challenges remain – just think about the increase in antibiotic resistance as one example. Innovation is essential to meet these new challenges.”