DEFINE PROBLEM

3. DEFINE PROBLEM

3.1. Improve Anti-tumor Activity of Doxorubicin by ‘‘Passive’’ Liposome Targeting

To successfully deliver an encapsulated drug to tumors, the liposome carrier must retain the drug while in blood, the med- ium through which the liposomes must pass to reach the tar- get. Moreover, the liposomes must recirculate for the period of time needed to access the tumor and possess the physical characteristics that allow them to actually enter the tumor.

The liposome literature of the late 1970s and early 1980s is replete with reports from the laboratories of liposome scientists who attempted to engineer liposomes to circulate longer in blood and remain intact while doing so. Bona fide structure =function relationships emerged from this work (4). For example, small ( <50 nm) liposomes composed of high phase transition lipids and cholesterol were found to resist degradation in blood and to circulate at least for a few hours in rodents (5). These results were later reproduced in human cancer patients (6). In the mid- 1980s surface modification of liposomes was explored as a strat- egy to improve recirculation times further. The rationale driving this approach was to create a liposome that behaved like a tiny- formed element in blood (i.e., an erythrocyte or platelet). Indeed, circulation times were significantly improved when specific gly-

colipids such as a brain-derived ganglioside (GM 1 ) or a plant phospholipid (hydrogenated phosphatidyl inositol) were included in the formulation (7,8). Moreover, prolonged circula- tion times were highly correlated with improved distribution

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Figure 1 Correlation between liposome circulation time and tumor uptake.

of liposomes to implanted tumors in mice (Fig. 1) (9). This find- ing confirmed the belief that reducing the rate of MPS uptake (increasing circulation time) would allow i.v. injected liposomes to access systemic tumors.

Following these hopeful developments with carbohydrate- coated liposomes, other surface modification approaches were pursued. The most promising results were achieved by grafting polymer groups to the liposome surface (10). Circulation half- lives in excess of 12 hr in rats were found with polyethylene glycol-coated liposome formulations ( Fig. 2 ) (11). A comparison of the pharmacokinetics in cancer patients among various liposome formulation is shown in Fig. 2 (6,12,13).

3.2. Provide Required Pharmaceutical Attributes Adequate shelf-life stability, a scalable, reproducible produc-

tion method and validation of sterility assurance methodology are required for any injectable pharmaceutical product.

With respect to stability, liposome products represent a special case. The safety and efficacy of the system is critically

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Figure 2 Human plasma pharmacokinetics of liposomes.

related to the encapsulated form of the drug. Indeed, toxicol- ogy studies required to qualify the product for clinical testing are performed on the encapsulated drug. Therefore, for the claimed shelf-life of a particular product, the drug must remain encapsulated (at least within predetermined limits). Any leakage during storage could, and very likely would, change the safety and efficacy profiles of the product, which is unacceptable from a regulatory perspective.

The reproducibility of production is also critical. Simple chemical entities must meet strict purity and potency stan- dards and all excipients must be of suitable quality. Physical characteristics of liposomes profoundly influence their phar- macology. So, in addition to chemical standards related to the active ingredient and excipients (including lipids), liposome products must reproducibly conform to equally strict physical specifications. These include percent encapsulation (i.e., amount of ‘‘free’’ or unencapsulated drug in the product— which regulators may rightly regard as a contaminant), amount of drug carried in each liposome (drug ‘‘loading,’’ usually expressed as mass or moles of drug per unit lipid), size, and the rate of release of the drug.

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Sterility assurance is another requirement that presents interesting challenges to the developers of injectable liposome products. In general, terminal sterilization with heat or ioniz- ing radiation is not possible in the case of liposome encapsu- lated drugs due to the sensitivity of the drug and =or the lipids to degradation under these conditions. Aseptic proces- sing is possible but validation is costly and burdensome. Terminal filter sterilization using reliable, industry-validated filtration systems is the method of choice.

3.3. Craft Regulatory Approval Strategy Any improvement of the anti-tumor activity of a drug pro-

vided by liposome encapsulation could be offset by an increase in any one of the side effects which limit the dose patients are able to tolerate. Well-designed and executed preclinical toxi- cology =pharmacology studies are absolutely necessary to provide reassurance that the therapeutic index of the encap- sulated drug is demonstrably superior to that of the unencap- sulated drug. Without such information, it would be foolhardy to embark on an expensive product development program.

Clinical development is generally the most expensive and time consuming element of the product development cycle. In the case of cytotoxic cancer drugs, registration is usually based on results obtained from the typical sequence of clinical trials. During Phase I, the safety profile and preferred dose and dosing schedule for the agent are established. Phase II trials fine tune the dose and confirm clinical activity in well- defined patient populations. The primary source of data required for approval is usually derived from ‘‘well-controlled’’ Phase III trials which are designed to demonstrate both safety and efficacy, usually relative to some established therapy.

For regular marketing approval of oncology drugs substantial evidence of efficacy from ‘‘adequate and well- controlled’’ trials is necessary. Pivotal registration trials must have a valid control (i.e., a population to which the results of the product under testing can be compared) and provide an objective, quantitative measurement of the drug’s effect.

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Endpoints typically are disease-free survival, overall survival or a surrogate for one of these. Optimally, from the perspec- tive of the regulatory authorities, the comparison would be to standard therapy in a blinded study (i.e., patients are pro- spectively randomized to the new product or the comparator without either the patient nor the caregiver knowing which one is actually administered). In some instances, standard therapy for a specific type of cancer is not officially approved, but support for the therapy as a standard of care has been established in the peer-reviewed literature.

At times, there are no proven therapeutic options that would be suitable to be used as a control arm of a comparative study. In non-life-threatening diseases, placebo controls are often used. In the case of cancer, placebos are understandably not acceptable to study participants and their physicians. In this case less optimal controls can be relied upon. Two differ- ent doses of the product could be compared with the prospect that one may provide greater benefit than the other. Histori- cally controlled trails rely upon a comparison of the benefit of the new drug in a specific tumor type to a series of retrospec- tively collected cases of the same cancer type treated with standard therapy. Although historical controls are appropri- ate at times, regulators generally regard them as a poor substitute for prospectively randomized trials. For example, the standard of care may have changed between the time the control patients were treated at the time the new drug was tested and there is no way of telling whether this influ- enced the outcome of the comparison. Nevertheless, several cancer drugs including paclitaxel have been approved on the basis of historically controlled trials (14).

Clearly the tumor type and patient population for clinical trails will be selected based on the sensitivity of the tumor to the encapsulated drug, patients’ tolerance of the product, and the therapeutic benefit provided by the product. If a mean- ingful clinical benefit can be established in a population of patients afflicted with a life-threatening tumor and who have exhausted all other treatment options, accelerated review by regulatory authorities and more rapid that normal approval may be an option.

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New Drug Application (NDA) regulations in the United States were modified in 1992 to include a provision (CFR Title

21, Part 314, Subpart H) which allows for accelerated approval of drugs intended to treat life-threatening diseases in situa- tions when the drug appears to provide benefit over available therapy, but does not meet the standards required of regular approval. With respect to cancer therapy, the example that is often cited is accelerated approval based on a surrogate end- point (e.g. partial response rate or time to tumor progression) which is likely to predict clinical benefit (e.g. complete response rate, survival) but not yet established to the degree that would

be required to support regular approval. As a condition, approvals based on Subpart H require the sponsor to conduct post-marketing trials to validate that the surrogate marker used actually does predict objective clinical benefit.

Accelerated marketing approval is an attractive option, for both small and large pharmaceutical companies. But there are many attendant risks. In the first place, if no proven treatment options exist in the selected clinical indication, there may not be an opportunity to compare the new liposo- mal drug product with an existing therapy. That is, rando- mized, comparative clinical trails, which represent the ‘‘gold standard’’ for pivotal registration trials, are not possible because there is no proper comparator. In this case, so-called ‘‘open-label’’ non-comparative trials must be relied upon for approval. In a real sense the comparator in this case is a his- torical understanding of the typical course of the disease pro- cess. For example, patients with advanced non-small cell lung cancer who have failed all standard chemotherapy do not typically improve spontaneously, but rather their disease progresses with a median survival time of only a few months. In such a population, if intervention with a liposomal anti- cancer drug (or any other drug for that matter) provides objective responses or demonstrable benefit to a reasonable number of patients, regulatory approval could be sought with- out the benefit of comparative data. Following this acceler- ated strategy, the burden of proving without question that the patients are truly refractory to existing therapy and that the benefit is meaningful to the patients falls squarely on the

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drug sponsor. But, if the liposomal drug product performs well, the design and execution of a clinical trials program aimed at accelerated approval is a real possibility.

Another potential shortcoming for an accelerated appro- val approach is that the approved use (label claim) will be limited to a small number of patients that fall into the chemo-refractory or salvage therapy categories. In this case, post-marketing studies are typically conducted to expand the label claims, and thus the market potential, for the product.