Incremental Innovation

"The FDA would like to offer patients a choice of drugs within the same class, since not every patient responds to every drug in the same manner."
Janet Woodcock, M.D., Director of the FDA Center for Drug Evaluation and Research (CDER)^[i]

As in most manufacturing and high-technology industries, pharmaceutical innovation often occurs as a series of incremental improvements in safety, efficacy, and utility with the same general "class" of medicines that together have a significant impact on patient care. Far from mere "me-too" drugs, these incremental advances give patients and physicians more and better options to provide treatment that best meets the individual's needs.

Tailoring Treatment to the Patient

Therapeutic Options

Physician and patient groups echo FDA's view

Incremental innovation is essential to continued pharmaceutical innovation

The Nature of Invention: Spotlight on Cancer Treatments

Clinical research is an incremental process that continues long after Food and Drug Administration (FDA) approval, which often marks the "starting point" for a number of additional studies of the therapy. As a larger body of evidence is developed through these studies, researchers learn not only how the drug works in the approved application but also how it may be used:

at other points in the treatment process
in other diseases
in combination with other treatments
in different patient subpopulations

Gleevec: Post-Marketing Research Shows Full Benefit of Cancer Drug

The timeline of approved indications for the cancer medicine imatinib (Gleevec®)^[1] is a good example of how the value and uses of a drug can increase as long-term studies continue to provide new data. Imatinib was originally approved based on surrogate endpoints, which are biological markers that show the drug is having an effect at the molecular level. Six years later, clinical study data showed 88% survival for patients on the drug, compared with 48% prior to taking imatinib.

Gleevec Approvals

2001 — May 2001: Initial Indication - Patients with Philadelphia chromosome-positive chronic myeloid leukemia (Ph+ CML) in blast crisis, accelerated phase, or chronic phase after failure of interferon-alpha therapy (IFN)

2002 — Feb 2002: Approval for patients with Kit (CD117)-positive unresectable (unable to be removed through surgery) and/or metastatic malignant gastrointestinal stromal tumors (GIST)

Dec 2002: Approval for newly diagnosed adult patients with Ph+ CML in chronic phase (CP)

2003 — May 2003: Approval for pediatric patients with Ph+ CML-CP recurrence after stem cell transplant or IFN resistance

2006 — Sept 2006: Approval for newly diagnosed pediatric patients with Ph+ CML-CP

Oct 2006: Five new indications, such as adult patients with relapsed or refractory Philadelphia chromosome-positive acute lymphoblastic leukemia (Ph+ ALL) and adult patients with unresectable, recurrent and/or metastatic dermatofi brosarcoma protuberans

2008 — Dec 2008: Approval for adjuvant treatment of adult patients following resection of Kit (CD117)-positive GIST

"The full clinical value of a cancer therapy is often much greater than recognized at the time of initial FDA approval."— Boston Healthcare

^[1] Boston Healthcare Associates, Recognizing Value in Oncology Innovation (Washington, DC: BHA, March 2010).

Tailoring Treatment to the Patient
Physicians see it everyday - patients respond differently to medicines. Giving doctors a choice from among the range of available prescription medicines is essential to enabling them to treat their patients effectively.

According to experts at Temple University School of Pharmacy, "Newer drugs in a therapeutic class often have fewer side effects, improved drug safety and effectiveness, and greater ease of use which facilitates compliance with prescribed therapeutic regimens. Product alternatives permit treatments to be better tailored to individual patient needs."

These improvements are especially important for optimal treatment of elderly patients because their diverse response to medications requires individualized care. A broad range of medicines provides physicians with a "tool chest" to treat each patient with precision and provides options when particular agents are ineffective or poorly tolerated by a given patient.

Therapeutic Options
Incremental innovations have improved treatments for many serious diseases, including cancer, cardiovascular diseases, diabetes, and arthritis. For example, for diseases of the central nervous system, overall response rates are often 50% or less.^[ii]

Patients who fail to respond to one drug will often respond to another drug in the class. Examples of widely used drug classes associated with great variation in patient response are the selective serotonin reuptake inhibitors (SSRIs), beta-blockers, and calcium channel blockers.

SSRIs: In patients treated with SSRI agents for depression, 26% of non-responders to fluoxetine did respond to sertraline. Conversely, another study reported that 63% of patients who failed to respond to sertraline^[iii] did respond to fluoxetine.^[iv]

Beta-blockers: The currently available beta-blockers offer differences in strength, effects on the nervous system, pharmacokinetic properties (which determine appropriateness for patients with impaired kidney or liver function), potential for interaction with other drugs, efficacy in specific racial groups, complexity of the dosage regimen, and side effects profile. The array of differences among these drugs enables doctors to customize treatment to the patient's specific needs.^[v]

Calcium channel blockers: This class is used for treatment of hypertension, chest pain, heart failure, stroke, and other cardiovascular conditions. However, different calcium channel blockers have different benefits and risks. For instance, two different calcium channel blockers may be similar in their effectiveness against hypertension and angina, but differ in the extent of their actions on various aspects of the circulatory system, such as heart rate, blood flow, and electrical conductivity of the heart.^[vi]

Physician and patient groups echo FDA's view of the importance of giving doctors and patients a wide choice of medicines

The National Medical Association (NMA) is urging policymakers to avoid decisions that limit doctors' ability to provide individualized care. "A 'one-drug-fits-all' approach to therapy does not take into account individual patient responses to medicines," NMA President L. Natalie Carroll, M.D., said in a recent press release. "New science is helping to identify differences in the ways individuals react to drug therapy. Any attempt to control spending should take such differences into account."^[vii]

Discussing the value of newer, so-called atypical antipsychotics to treat schizophrenia and other mental disorders in a May 20, 2003 story in The New York Times, Dr. Joseph Parks, medical director of Missouri's Department of Mental Health, stated: "They are good medications, and they seriously help a lot of people. I would not want to give up any of them."

Incremental innovation is essential to continued pharmaceutical discovery
"The process of continuous incremental improvement is the predominant mechanism of technological innovation and product development in most manufacturing and high technology industries," the Temple University report notes. "Incremental innovation has been an especially important source of progress in the pharmaceutical industry. The vast majority of clinically important drugs developed over the last 50 years have resulted from an evolutionary process, involving multiple, small, successive improvements within a pharmacological class."

^[i] Tanuja Koppal, Ph.D. How CDER's Janet Woodcock helps drug companies achieve compliance, speed the drug review process, and improve time to market for new drugs - Inside the FDA: November 01, 2002.

^[ii] Williams, J.W. Jr., et al. (1999). Treatment of Depression: Newer Pharmacotherapies. Publication No. 99-E014. Agency for Health Care Policy and Research, U.S. Department of Health and Human Services, Rockville, MD.

^[iii] Zarate, C.A., Kando J.C., and Toben M., et al. (1996). Does Intolerance or Lack of Response With Fluoxetine Predict the Same Will Happen With Sertraline? Journal of Clinical Psychiatry, 57:67-71.

^[iv] Thase, M.E., Blomgren, S.I. and Birkett, M.A., et al. (1997). Fluoxetine Treatment of Patients with Major Depressive Disorder Who Failed Initial Treatment with Sertraline. Journal of Clinical Psychiatry, 58:16-21.

^[v] Albert Wertheimer et al., "Too Many Drugs? The Clinical and Economic value of Incremental Innovations," Investing in Health: The Social and Economic Benefits of Health Care Innovation, Volume 14, pages 77-118.

^[vi] A. Werthemier, R. Levy, and T. W. O'Connor, op cit.

^[vii] National Medical Association/National Pharmaceutical Council press release, "Study Shows that Genetic Differences in Minorities May Cause Varied Reactions to Medicines," September 25, 2002.