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The Drug Development Process

Key Facts • Research and Development Time to develop a drug = 10–15 years • Development Costs: – Cost to develop a drug • 2001 = $802 million2 • 1987 = $318 million • 1975 = $138 million

– • Cost to develop a biologic • 2006 = $1.2 billion

R&D Spending Year

PhRMA Members

Total Industry


$43.0 billion (est.)

$55.2 billion (est.)






Not available



Not available



Not available



Not available

Percentage of Sales That Went to R&D in 2006 Domestic R&D as a percentage of domestic sales = 19.4% Total R&D as a percentage of total sales = 17.5%

Total National Institutes of Health Funding (Part of this budget is allotted for developing drugs.) • 2007 = $28.6 billion • 2006 = $28.5 billion • 2005 = $28.7 billion

Approvals • Drugs approved in 2006 = 299 • Only 3 of 10 marketed drugs ever produce revenues that match or exceed R&D costs. • Between 1995 and 2005, over 160 orphan drugs were approved. • Average effective patent life for pharmaceuticals= 11.5 years

Value of Medicines • New medicines generated 40 percent of the two-year gain in life expectancy achieved in 52 countries between 1986 and 2000. • A recent study found that the return on investment (ROI) for a 20 percent increase in adherence was substantial for disease-related costs: for every $1 spent on diabetes medicines, there were $7.10 in savings; the savings for $1 spent on cholesterol medicines was $5.10; and, for every $1 spent on blood pressure drugs, $4 in savings resulted. • Every additional dollar spent on health care in the United States over the past 20 years has produced health gains worth $2.40 to $3.

Sales • Total number of U.S. prescriptions October 2004 September 2005 = 3.6 billion • Generic share of market by volume (generic/brand, weighted average)

July 2005 = 54/46 2006 = 58/42 (estimated)

“There’s nothing more innovative than working in the pharmaceutical industry right now. There’s nothing more exploratory. There are no frontiers that are more open than those that exist in our business right now.” —Andrew Dahlem, Ph.D., Eli Lilly and Company, Vice President, Toxicology/ Drug Disposition and Pharmacokinetics

Expenditures ( Billion of Dollars)

Biopharmaceutical Companies Are Investing More in Research and Development

Sources: Burrill & Company, analysis for Pharmaceutical Research and Manufacturers of America, 2007; and Pharmaceutical Research and Manufacturers of America, PhRMA Annual Member Survey (Washington, DC: PhRMA, 2007). *The “Biopharmaceutical R&D” figures include PhRMA research associates and nonmembers; these are not included in “PhRMA Member Companies’ R&D Expenditures.” PhRMA first reported this data in 2004.

The Cost of Innovation Developing a new medicine is a long and costly process. The chances of success are very low. There are many estimates of the cost of developing a drug, but one of the most-cited studies is from the Tufts Center for the Study of Drug Development, which put the average cost of developing a new drug at $802 million (in year 2000 dollars), including the cost of failures and capital. The Tufts Center also recently estimated the cost of developing a biologic (a medicine generally composed of large and complex molecules, produced by a biological system) to be $1.2 billion (in year 2005 dollars).

Most Leads Don’t Become Medicines Statistics show that most candidate drugs never make it to the medicine cabinet. In fact: • Only 1 in 5,000–10,000 compounds tested eventually reaches consumers. • Only 1 of every 5 compounds that enter clinical testing reaches the market. • Only 3 of 10 drugs that reach the market ever earn enough money to match or exceed the average R&D cost per new medicine.

Drug Development Costs

Note: The Tufts Center for the Study of Drug Development has updated its $802 million estimate by adjusting for annual rate of R&D increases and inflation. That estimate is available at Source: J. A. DiMasi, “Tufts Center for the Study of Drug Development Pegs Cost of a New Prescription Medicine at $802 Million,� press release, 30 November 2001.

The New Drug R&D Process Phase IV: FDA Review, Large Scale manufacturing

1 FDA Approved Drug NDA Submitted

Phase I : 20-100 Volunteers IND Application

Preclinical: 250 Compounds

Drug Discovery: 5000-10000 Compounds

10-15 years

Phase II: 100-500 Volunteers

5 Compounds

Phase III: 1000-5000 Volunteers

PRE-DISCOVERY • Understand the Disease to be Treated. What are its causes, molecular pathways, and effects?

• Identify a Drug “Target.” What gene or protein should the new drug affect?

• Test the Target for Research Feasibility. Is the target really involved in the disease process? Can a drug act on the target?

Drug Discovery • Find a Candidate Drug or “Lead.” What molecule may act on the target to change disease course? • Conduct Initial Tests on Every Promising Compound. – Is the compound nontoxic? – Can it be absorbed into the bloodstream? – Distributed to the proper site in the body? – Metabolized? • Optimize Remaining Leads for Safety and Effectiveness. Are any of the hundreds of possible chemical variations of a lead more effective against the target or less toxic?

Pre-clinical Test Leads in the Laboratory and in Animals. How does the candidate drug work? Is it safe enough for testing in humans?

Develop and Test Process to Make Drugs for Clinical Trials. What “recipe� and form should it have for human use? How can we make enough of the drug for patient testing?

IND Application and Submission File an Investigational New Drug (IND) Application with the Food and Drug Administration (FDA). What is the new drug’s chemical structure? Mechanism of action? Side effects? What is the research plan for clinical trials?

FDA and IRB (Institutional Review Board) Reviews Are risks to clinical trial participants reasonable? Are plans for informed consent and monitoring/ reporting adequate?

Clinical trials • Conduct Phase I Trials (20–100 healthy volunteers). Is the candidate medicine safe in humans? How is the drug metabolized by the body? What is the safe dosing range? Should it move into further development?

• Conduct Phase II Trials (100–500 volunteers with the target condition). Does the drug improve the patients’ condition? What are its side effects? Does it have the anticipated mechanism of action? What are the most safe and effective doses and dosing schedules?

• Conduct Phase III Trials (1,000–5,000 volunteers with the target condition). Does the drug show statistically significant safety and benefit? Is the medicine safe over time?

FDA Review • Submit New Drug Application (NDA), which includes up to 100,000 pages of information on research findings, analysis of clinical trial results, and proposed labeling and manufacturing plan. – Is the new drug safe and effective enough to be approved for use? – Are more studies or information needed before a decision can be made? – Does the proposed manufacturing process ensure product safety and integrity?

Large-Scale Manufacturing Create and Perfect a Large-Scale Manufacturing Process. – How can we move from smaller-scale production to large quantities of labeled, packaged products ready for distribution? – How can we guarantee that each tablet will contain the correct amount of the drug without impurities? – How can we ensure manufactured product safety?

• Create a Customized Manufacturing Facility. – Is a new facility needed, or can an existing facility be adapted? – Does the manufacturing facility comply with good manufacturing practices set out by the FDA?

• Create a (Sometimes Global) Distribution Process.

Ongoing Surveillance Monitor Product Experience and Report to the FDA. • What happens when large numbers of patients use the drug? • Do any adverse events occur? In some cases, the FDA asks companies to conduct Phase IV clinical trials to assess long-term drug safety or effectiveness in specific patient populations (e.g., older people, women).

Innovative Approaches Characterize New Medicines in Development Disease/Condition

Candidate Medicine Approach

Potential Benefit

Alzheimer’s disease

Blocking the production of beta amyloid protein, which is thought to be a cause of Alzheimer’s, and inhibiting the degradation of acetylcholine, which is thought to improve memory.

Improve Alzheimer’s symptoms and reduce progression of disease.

Breast Cancer

Reducing the amount of the Bcl-2 protein in cancer cells.

Enhance effectiveness of chemotherapy.

Colorectal cancer

Using a monoclonal antibody to target the epidermal growth factor receptor.

Stop the growth of cancer cells and kill existing cells.

Coronary artery disease

Injecting a gene that promotes blood vessel growth.

Allow patients to grow their own coronary bypass and reduce the need for surgery.

Cocaine Addiction

Using a vaccine to induce cocaine-specific antibodies that bind to cocaine in the blood, blocking its uptake into the brain.

Reduce cocaine effects, allowing patients to break the cycle of addiction.

Lennox-Gastaut syndrome (a rare disorder that is a severe form of epilepsy in which seizures usually begin before four years of age)

Structurally unrelated to any other drug available, this drug is thought to affect calcium channels of neurons.

Make dosing easier through a wide therapeutic window.

Orphan Drugs Advance Treatment for Rare Diseases Disease


Treatment/ Advance(s)

Gaucher’s disease

A metabolic disorder in which the body cannot break down glucosylceramide. Can cause bruising, enlarged liver and spleen, weakened skeleton, and lung and kidney impairment

A new oral treatment has been developed for patients who cannot tolerate existing treatment.

Pulmonary hypertension

Continuous high blood pressure in the pulmonary artery, leading to narrowing, clots, and weakening of the heart muscle

Three new treatments in the last decade increase exercise ability and decrease symptoms for patients with varying degrees of disease severity.

Crohn’s disease

Abdominal pain, chronic diarrhea, loss of appetite, weight loss, joint aches, and fatigue.

The first-ever treatment, a genetically engineered antibody that reduces bowel inflammation and symptoms, has been developed.

The Drug Development Process