Trastuzumab

New knowledge of genetic biomarkers for disease is spurring the development of pharmacogenomic-based drugs and biological products and also raising new challenges for the Food and Drug Administration and for pharmaceutical manufacturers. Genomics information promises to spur discovery of more individualized dosages and treatment regimens by identifying patients with certain conditions that make them more likely to respond to certain medicines as well as those individuals susceptible to adverse events.

Manufacturers can use this information to select high-response individuals for clinical trials, an approach that promises to reduce clinical research costs, accelerate drug development, and promote appropriate and safe complex new treatments. Linking pharmacogenomic therapies to diagnostic tests also may help convince health plans and payers that certain expensive therapies are cost-effective and should be listed on plan formularies (see sidebar, "Pharmacological effects influence Medicare guidelines").

FDA is eager to encourage more industry use of pharmacogenomic (PG) data in drug development to achieve these benefits. In November 2003, the agency issued a draft guidance designed to prompt pharma companies to voluntarily share internally developed PG information with FDA to help the agency and the research community keep abreast of genomics developments and establish new genetic biomarkers (see Washington Report, February 2004). Manufacturers acknowledge that they are using such information to better understand the metabolic effects of test therapies and to identify appropriate patients for clinical trials. Most companies, though, are reluctant to submit these data to FDA for fear of raising questions that could delay product approval or limit the approved label.

The data submissions guidance, which FDA plans to finalize by next year, would allow sponsors to submit voluntary genomic data submissions for analysis by a special FDA review group, in a process separate from the established new drug review. This Interdisciplinary Pharmacogenomics Review Group would examine such data without considering it as part of the formal market application. Some companies already are sharing PG data with the FDA panel, and the agency is clarifying procedures to encourage other firms to do the same.

Diagnostics critical

Manufacturers may be reluctant to share PG data with FDA, however, if they fear that information about new biomarkers might prompt the agency to require a company to codevelop a diagnostic test to bring a new pharmacogenomic treatment to market. The emergence of more genomic markers that can identify high- and low-responding patients is prompting regulators to seek development of diagnostic tests able to determine which patients should be treated with a therapy, the risks associated with treatment, and the appropriate dose.

FDA Acting Deputy Director Janet Woodcock is spearheading an effort to issue guidance about this subject. The proposal would clarify how FDA will regulate diagnostics and pharmacologic interventions that may be developed by various manufacturers and traditionally are considered separate items for regulatory, reimbursement, and clinical practice purposes. Various FDA centers regulate medical devices, drugs, and biologics, but the growing number of medical products that involve multiple components prompted the agency to establish a central Office of Combination Products (OCP) (see sidebar, "FDA clarifies policies for combination treatments").

Although some FDA staffers would like to require the use of a diagnostic for any PG therapy with an identifiable biomarker, manufacturers seek a more flexible approach to codevelopment that recognizes the significant differences in processes and practices for developing diagnostics (Dx) as compared with drugs and biologics (Rx).

While still crafting a formal policy, FDA has begun to examine whether new drug applications and therapies on the market may require labeling changes to reflect new PG information and testing opportunities. Larry Lesko, director of the Office of Clinical Pharmacology and Biopharmaceutics in the Center for Drug Evaluation and Research (CDER), notes that before approving "Stranera," Eli Lilly's drug for treating attention deficit disorder, last year, FDA asked Lilly to include in the label a reference to a laboratory test that could screen for poor metabolizers of a certain enzyme. Similarly manufacturers of biopurines are revising labels to include in formation about a test for an enzyme deficiency. In addition, FDA is monitoring adverse-event reports to identify approved drugs with safety problems that might benefit from label changes informing clinicians of genomic tests that can identify patients likely to have difficulties using a certain therapy.

Pathways for partners

Manufacturers and FDA officials from CDER and the Center for Devices and Radiological Health discussed these issues and options for policy development at a July 2004 workshop "Codevelopment of Drug, Biological, and Device Products" cosponsored by FDA and the Drug Information Association (DIA). Although Woodcock believes that clearer FDA policies will encourage more innovative re search in this area, the overriding concern for manufacturers is that FDA might require them to codevelop a diagnostic test to gain approval of a new therapy.

At the workshop, manufacturers objected to drug-device development approaches similar to procedures that FDA has put in place for combination products. Lois Hinman, director of regulatory affairs at Hoffman LaRoche, noted that the term combination product does not fit the Rx-Dx model very well because it implies simultaneous product development and approval. She preferred to describe drugs linked to diagnostics as partner products that may be developed and produced by different companies and regulated separately by FDA. "Flexibility is key," Hinman said. She believes FDA should develop guidance that describes multiple development scenarios:

* Dx first. A medical device manufacturer independently develops a diagnostic that a drug manufacturer could use in a clinical program. FDA then would approve the new drug labeled for use with the diagnostic.

* Rx first. The pharmaceutical company does not discover a biomarker until later in drug development, possibly Phase 3 or postapproval. The drug maker seeks approval of the drug without a specific diagnostic, then applies for a label change after Dx development and approval.

* Simultaneous Rx-Dx. The drug maker explores biomarker strategies early in development, leading to a new validated biomarker that can be tested with a new diagnostic. FDA would review drug and diagnostic products simultaneously and approve both products with cross-references in their labels.

Manufacturers insist codevelopment arrangements involving drug and diagnostic firms must be voluntary. Industry wants FDA to present substantial evidence of medical need and of a diagnostic's ability to improve safety or efficacy in a target population before requesting Rx-Dx codevelopment. Manufacturers also want clear processes to follow for undertaking such codevelopment, including a schedule of critical FDA meetings and clarification of which FDA offices will be revolved and how they will be coordinated.

Manufacturers believe that linked labeling, instead of codevelopment, may be the most appropriate way to deal with drugs that can benefit from patient testing. The labels of the two products would describe their coordinated use, but product approval would be separate, even if it occurred simultaneously.

A codevelopment model

A prime example of the issues involved in drug-diagnostic codevelopment is the process followed by Genentech in bringing to market "Herceptin," a monoclonal antibody that can treat about 25% of breast cancer patients who have a genetic abnormality that leads to HER2 protein overexpression. FDA and Genentech recognized during product development that appropriate treatment required a diagnostic test able to identify HER2-positive individuals. Genentech devised an assay for selecting patients for clinical trials, but to gain market approval, FDA wanted the company to provide an HER2 diagnostic test suitable for commercial use. Genentech initially partnered with DAKO Corporation to provide such a test; the two manufacturers simultaneously filed applications for coordinated use of the drug and the diagnostic and gained FDA approval in late 1998.

After Herceptin was on the market, though, Genentech found that the medical community remained uncertain about when it was appropriate to test patients for HER2, explains Cheryl Madsen, Genentech senior manager for regulatory affairs. Further research found that a test method based on fluorescence in situ hybridization (FISH) could better select those patients who could clearly benefit from Herceptin. Genentech partnered with the diagnostic firm Vysis to gain FDA approval of a new FISH diagnostic and applied to FDA to change the label for Herceptin to include FISH testing as an alternative.

Diagnostic manufacturers are developing more tests to identify suitable participants for trials of new cancer therapies and other drugs. Such collaborations are successful when they begin early in drug development, points out DAKO clinical affairs director Gretchen Murray. This headstart allows drug manufacturers to incorporate diagnostic statistical requirements into development programs to ensure that clinical study specimens are banked and stored appropriately.

Woodcock recognizes that it would be difficult for FDA to require codevelopment of drugs and diagnostics. But if a therapy such as Genentech's Herceptin (trastuzumab) works only for certain patients, she believes that the manufacturer must identify that subgroup. Although Woodcock sympathizes with industry's concern that codevelopment requirements could increase the cost and time involved in bringing a new therapy to market, she maintains that diagnostics will be key to launching more targeted treatments and that industry can benefit greatly from such approaches. If a manufacturer can identify the genetic factors related to a drug's efficacy, for example, the company may he able to get very high response rates from very small clinical trials, she explains. And the ability to test for a genetic predisposition to serious adverse events can eliminate those individuals from studies and treatment and enhance the satiety profile of a product. Such efforts may permit FDA to approve some therapies that otherwise might never reach the market.

Even if FDA does not require pharma companies to comarket a diagnostic test, insurers and health plans may pressure industry to do so, predicts CDER director of medical policy Robert Temple. For very expensive therapies, he observes, payers will want a diagnostic to better target such drugs to the most appropriate patients.

Codevelopment provides a real opportunity to improve medical outcomes, Woodcock said at the FDA-DIA work shop. She emphasized how important it is for FDA policy makers to "get this right." All these issues are slated for further discussion at an industry workshop on pharmacogenomics issues scheduled for April 2005. FDA and the Pharmaceutical Research and Manufacturers of America held meetings on this topic in May 2002 and November 2003 and recognize that another session is warranted, particularly if at that time FDA can unveil a final guidance on voluntary data submission and a draft guidance on drug-diagnostic codevelopment.

Pharmacological effects influence Medical guidelines

By a quirk of legislative fate, last year's Medicare Modernization Act assigned to USP the critical task of defining drug classes and categories in a model guideline for drug plan formularies. This guideline will shape coverage and prices of prescription drugs for some 40 million Medicare beneficiaries and will influence coverage decisions by managed care organizations, employers, and other healthcare purchases.

Although insurers and pharmaceutical benefit managers (PBMs) sponsoring Medicare prescription drug plans (PDPs) won't have to adhere to the modal formulary, the guidelines will provide a safe harbor, and plans will have to justify alternative approaches.

With the stakes so high, USP has tried to be highly transparent and all-inclusive in its policy-development process. An expert panel chaired by USP CEO Roger Williams has met with interest groups and has examined leading formularies and international disease classification models. In mid-August, the group posted a draft classification system with 43 major therapeutic categories and 138 pharmacologic drug classes If this USP system is adopted, PDP formularies would offer at least two drugs in each class. To broaden coverage, the panel also proposed a third column of recommended drug-class subdivisions, a highly controversial approach that would allow plan sponsors determine coverage for many important drugs, including newer antidepressants, insulins, and ACE inhibitors.

More or less

Pharma manufacturers prefer formularies with some 200 categories and classes to increase the number of listed products and to minimize competitive bidding. PBMs and insurers back models with about 50 classes to gain more negotiating leverage. At a public meeting in August, participants on all sides criticized the USP proposal. PBMs and insurers warned that overly detailed coverage requirements will make it impossible to offer affordable benefits and demanded flexibility in shaping formularies and drug plans. Manufacturers, disease groups, medical experts, and patient organizations argued that seniors have special health needs and need access to a broad range of medicines. Pharma companies blasted the proposal as likely to exclude patient access to statins, antidepressants, important antihypertensive medications, oral diabetes treatments, and new osteoporosis medicines.

In calling for a range of choices for patients, these groups emphasized important differences in the pharmacological effects of medicines within the same class. The USP panel planned to review all these and other comments and submit a more complete proposal to Medicare in November. The USP group is scheduled to publish a final guideline by the end of the year; then it will be up to Medicare officials to incorporate the formulary plan into its broader prescription drug coverage program.

FDA clarifies policies for combination treatments

FDA established an Office of Combination Products (OCP) in the commissioner's office two years ago to oversee regulation of drug-biologic-device combination products. OCP provides a forum for deciding which FDA center should lead regulation of such products, an issue of particular concern to device manufacturers that often prefer to have their products reviewed by FDA's Center for Devices and Radiological Health.

Not all drugs and devices used together qualify as combination products, explained OCP associate director Patricia Love at the FDA-DIA workshop. The two components must be physically or chemically combined, packaged together, or have labeling for both products that require combined use to achieve an intended effect. True combos include drug-eluting stents and prefined syringes, as well as drugs that can be used only after conducting a specific diagnostic test.

When a manufacturer plans to seek FDA approval of a combination product, it can request that OCP decide which FDA center should take the lead in regulatory review. OCP makes such determinations on the basis of a product's primary mode of action, a tricky and often controversial process that FDA outlined in a proposed rule issued in May 2004.After OCP decides the basic oversight scenario for a new combo, it continues to monitor the review process and can resolve disputes involving FDA staff and sponsors.

OCP is wrestling with several tricky issues, such as whether a manufacturer needs to file one application with FDA for a combination product or separate applications for each component. OCP jurisdictional decisions affect several critical regulatory issues such as user fee payments and postapproval compliance requirements. This includes policies for submitting adverse event reports, for meeting good manufacturing practices, and for regulating marketing and promotional activities. OCP is developing guidance documents to address these issues. Additional information is available at www.fda.gov/oc/combination/default.htm.

Jill Wechsler is Pharmaceutical Technology's Washington editor, 7715 Rocton Ave., Chevy Chase, MD 20815, tel. 301.656.4634, jwechsler@edvanstar.com.

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