Special Studies

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A wide variety of specialized studies are conducted during the drug development process (Fig. 5.12). Interaction studies include the impact of either food, other concomitant drugs, or disease on the new product when the new drug is used in these situations. Investigator-initiated studies are protocols written by a possible principal investigator and submitted to the company for approval and funding. Pharmacoeconomic and quality of life are done within health care systems or universities that have the special expertise and access to the added data on costs of care or nonclinical assessments for such trials. Pharmacogenetic studies are becoming a new requirement as we learn about ethnic and genetic differences in the population related to the actions of products, both safety and efficacy.

r Effect of meals on absorption (if drug taken by mouth)

r Interactions between new drug and other medications (e.g., Coumadin; drugs that alter activity of cytochrome P450 [CYP] isoenzymes, if drug is metabolized by these enzymes)

r Effects of disease

Fig. 5.13. Food/Drug/Disease Interaction Studies

Phase 3b or 4 studies may examine the effect of a meal on absorption (if the drug is taken by mouth), including increases and decreases in blood levels, or its ability to reduce abdominal reactions like nausea (Fig. 5.13). Interactions between the new drug and other medications that would likely be used concomitantly are studied in phase 3b and phase 4, for example, warfarin; drugs that alter the activity of cytochrome P450 (CYP) isoenzymes, if the drug is metabolized by these enzymes. Many drug categories have impact on the CYP family of degradative liver enzymes and increase or decrease blood levels of concurrent drugs, such as antidepressants, beta-blockers, calcium channel blockers, narcotic analgesics, antipsychotics, estrogens, and nonsteroidal anti-inflammatory drugs. The effects of age may influence sensitivity to side effects, alter metabolism, or change patients' responsiveness. Diseases, especially liver, kidney, and heart, may change the pharmacokinetics of the new product, especially elimination, and side effects.

Investigator-initiated studies can be a valuable complement to the studies required by the FDA during the pre- and postap-proval periods (Fig. 5.14). Investigator-initiated studies explore different uses, doses, or patient subsets, as well as basic physiologic and disease mechanisms. At the same time, the pool of investigators and thought leaders familiar with the new drug is expanded. Investigators planning to do a study using either an unapproved drug or an approved drug for an unapproved use must obtain an investigator IND. Permission to do the study must be obtained first from the holder of the original IND. Once that has been accomplished, the process for obtaining an investigator IND from the FDA is relatively simple because the FDA can reference the original IND file. A formal submission, which includes the proposed study protocol and the investigator's qualifications, is made to the FDA.

r Goals:

c Explore different uses, doses or patient subsets r Explore basic physiologic and pathophysiologic mechanisms r Expand investigator pool, including thought-leaders r Specific investigator and manufacturer requirements:

c Investigator IND (reference company file) c Reports to FDA and company r Company may assist with study design and adverse event reporting, may provide drug, and may provide funding

Fig. 5.14. Investigator Initiated Trials r Definition: Study of net economic impact of drug selection and use on total cost of delivering health care r Health care utilization (efficiency) vs. efficacy and safety r "Value" - a benefit for money spent r Perceptions of value (multivariate concept) based on:

o Perspective: patient, provider, payer, or society

^ Type of therapy, eg, new/unique vs. add-on vs. me too

^ Costs and consequences, plus economic, clinical, humanistic outcome dimensions r Multiple study designs:

o cost-effectiveness, cost-minimization, cost-utility, cost-benefit r Role of FDA varies

Fig. 5.15. Pharmacoeconomics

After receiving the investigator IND, the investigator makes yearly reports to the FDA and submits any proposed changes to the protocol and any new protocols to both the FDA and the institutional review board (IRB) of record. Reports are also provided to the holder of the original IND, which are usually requested and often required by them.

The holder of the original IND (e.g., a pharmaceutical or biotech company) may assist with study design and adverse event reporting and provide study drug, especially before approval. The company grants permission for use of their product with the usual stipulations of review and even approval of the protocol, some agreement on the investigator(s)' input on any publications, and maintenance of patent rights at the company (a controversial subject). The company often also will provide some grant funding. However, the holder of the inves-tigational IND is ultimately responsible for all activities that occur related to the study.

Pharmacoeconomic (PE) studies have become increasingly important in health care decisions for product usage in health systems and therefore for the drug development process (Fig. 5.15). They are now often incorporated into phase 3 study plans, in parallel studies, or as part of the pivotal phase 3

study. Because there are many different PE studies, they are time-consuming and expensive, they use different data than typical phase 3 trials, and they are a key component of phase 4 studies. One definition of pharmacoeconomics is the study of the net economic impact of pharmaceutical selection and use on the total cost of delivering health care [8]. A key concept in economic analyses is "value." Value can be defined as a desirable outcome or benefit for a given therapy at a certain cost. The type of product also effects value, such that a novel therapy versus a good alternative has a greater value than a "me-too" product. The assessment of value is based on one's measurement criteria and the person making that assessment. Patient, physician, health care provider, payor, or health care system have different perspectives and information needs within the realm of pharmacoeconomics. Pharmacoeconomic (PE) studies utilize several different study designs including cost-effectiveness, cost-minimization, cost-utility, and cost-benefit. Examples of each are provided below.

The regulatory role of government agencies, such as the FDA, in PE studies is variable because such studies are not requirements at all for approval of the product for marketing. Regulators may lack the expertise in assessing PE studies, and guidelines are not available for all product types and study types. However in Europe and other parts of the world, an additional government agency often exists, such as a pricing or health care payment agency, that will approve government payments for drugs and devices. Because most countries have significant government payment for medical care, the responsible agency needs to be favorably influenced by PE data, additionally motivating a company to perform these studies in their phase 3 and 4 plans [8-12].

These four types of PE studies are outlined in Figs. 5.16 and 5.17 with five elements; the name of method, a brief definition, typical outcome measures used, a description of types of results expected, and then advantages and disadvantages of the designs or utility of the information. Cost-effectiveness analysis is the pharmacoeconomic study most frequently used. In this type of analysis, the cost and consequences of two alternative treatments are compared and quantified. The additional cost that an alternative treatment imposes over another treatment is compared to the additional effectiveness (in terms of outcomes) the treatment provides. The main objective of cost-effectiveness analysis is to evaluate the ratio between the cost surplus associated with the new treatment (e.g., the higher cost of the new pharmacological treatment) and the efficacy/effectiveness surplus derived from it.

Cost effectiveness ratio = -—tf,——-f-—--—--

(Clinical success treatment B)

One example of a cost-effectiveness analysis is the treatment of diabetes. Patients who are overweight often require weight reduction to improve their diabetes. A cost effectiveness analysis could examine the cost of adding to standard




1. Cost



Comparison of costs of alternative therapies (a ratio)

r Assumed clinical outcomes to be equal r Drug costs

' Show lowest cost among those of equal benefit



"r Simple cost analysis

r Outcomes of alternative treatments must be shown to be equivalent




2. Cost



Ratio of costs & benefits from alternative therapies (a cost /a outcome)

r Costs expressed as monetary units r Benefits are measured as specific outcomes ' Years of life saved can be given cost per specific unit



r Applicable to wide range of possible clinical outcomes r Used to compare drugs with same outcomes

r Comparisons among studies or diseases need to be same outcomes

Fig. 5.16. Pharmacoeconomic (PE) Studies 1 & 2





Ratio of costs & benefits from alternative therapies

r Outcome includes patient preferences (QALYs) - Cost = monetary units & benefits = preferences r Gives cost per QALY or similar measure including patient preferences

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