From The Lab To The Patient
In this issue of the Biotech Primer WEEKLY we will recap the past seven issues that highlight the journey a molecule takes from the lab to the patient.
Beginning in the 1980’s, scientists took a new tack in developing drugs. They adopted an approach known as rational drug discovery. Using this methodology, researchers first seek to understand a disease at the cellular level to identify its mechanism. Once the cellular mechanism becomes clear, scientists can identify a drug target: the molecule involved in the illness that the ‘as yet undeveloped drug’ will hopefully act on.
Fast forward many years and hundreds of millions of dollars and drum roll please… the ‘as yet undeveloped drug’ may just become the drug that cures your once incurable illness.
Drug Discovery: Identify And Verify
Researchers identify their molecular targets by answering one incredibly complex question: How does diseased tissue differ from healthy tissue?
Researchers verify the suitability of target molecules by answering two important questions: does the target play a key role in the disease? and will targeting the molecule likely be safe and effective?
Identifying and validating drug targets are only the first steps on the long road to safe, effective new medicines.
Drug Discovery: Hit To Lead
To find the best drug candidate, scientists need to design easy-to-perform, large-scale, fast, and accurate assays. Think automation. Think high throughput screening.
High throughput screening ideally results in several promising drug candidates or “hits.” To become “leads” that merit animal testing, hits must pass rigorous in vitro testing. On this leg of the drug discovery voyage, researchers ask three questions:
1. Is the hit safe?
2. Is the hit specific to the target?
3. Does the hit show promise to treat the disease?
Biopharma companies typically put lead compounds through several rounds of optimization before they can become drug candidates for preclinical testing. Lead optimization is the process by which a drug candidate is designed via iterative rounds of synthesis.
Drug Discovery: Safety and Submission
In vivo testing (“in a living thing”) comes next. This area of preclinical testing assesses a drug candidate’s toxicity in at least two different species of animals, such as mice and guinea pigs. The animals receive more of the drug for longer than would human volunteers. Meanwhile, lab technicians watch the animals for adverse effects. Preclinical testing must follow the FDA’s Good Laboratory Practice (GLP) guidelines. These regulations help ensure scientific integrity and humane treatment of laboratory animals.
Once researchers amass enough safety data to ensure that a drug candidate will be safe for people, they submit an Investigational New Drug (IND) application to the FDA. If the FDA blesses the application, the drug candidate may enter Phase 1 clinical testing.
Phase I/II: May The Odds Be In Your Favor
Every drug in clinical use today, from the latest CAR-T treatment to older cholesterol-lowering statins, share one thing in common: they have all successfully navigated the rigorous clinical trials process. This is no small feat, as only ~10% of the drugs that enter Phase I testing successfully emerge as marketed products. Those few drugs that show remarkable success in early clinical trials make headlines, and deservedly so.
Phase III: Choices, Choices, Choices
Phase III clinical trials continue to test a treatment’s efficacy and safety, but in still larger groups of patients. Bigger groups mean more statistically significant results. As in Phase II, the trials have traditionally been randomized, double-blind studies. If the investigational drug appears to work, patients are allowed to continue taking the medication after the trial ends, before regulatory approval. This is an example of what doctors and other medical professionals call compassionate use.
Choices, choices, choices… In addition to randomized, double-blind trials, researchers have other study designs at their disposal, which we will explore below.
Phase IV: That Something Special
The FDA’s special designations include:
Accelerated Approval allows drugs to go forward using surrogate endpoints instead of clinical endpoints. Surrogate endpoints, such as lowered blood pressure or reduced tumor size predict rather than demonstrate clinical benefits. In these cases, pharmaceutical companies must run post-market studies to verify the anticipated effect.
Priority Review means the FDA will aim for a decision within six months.
Fast Track is based on preclinical or clinical data that suggests the product addresses a specified unmet medical need. The designation enables developers to communicate more often with the FDA. The agency provides guidance on clinical trial design and process, which helps resolve questions or issues quickly. These designees also qualify for Accelerated Approval, Priority Review, and Rolling Review—which allows developers to submit each section of an New Drug Application (NDA) or Biologics License Agreement (BLA) as they finish, rather than all at once.
Breakthrough Therapy designates drugs that may greatly improve patient health. The bar is set high to join this privileged group, though. It requires preliminary clinical evidence of effectiveness. Once granted, Breakthrough designees receive Fast Track advantages, as well as intensive guidance on their development program as early as Phase I. They also get an “organizational commitment involving senior FDA managers,” according to the FDA website.
Getting Medications To Patients: Market Access
Market access is the process of proving a product’s value to ensure reimbursement with commercial payors, government payors and integrated delivery systems. These payor stakeholders are often referred to as “organized customer groups.”
According to Linda Lander, President of Inside Out Market Access, “market access aligns incentives between payors, pharmaceutical companies, providers, and patients to lead to cost-effective models.”
Emily Burke, PhD has worked in biopharma for 20 years, gaining science writing experience at The Scripps Research Institute and Ionis Pharmaceuticals. As a Ph.D. molecular biologist, she is passionate about advancing the public’s understanding of science. In addition to being a self-proclaimed “science geek,” she is regularly asked to speak at international scientific meetings. When not teaching and writing the WEEKLY for Biotech Primer, Dr. Burke swims with her swim club and performs regularly on the improv circuit in San Diego.