FDA Encourages Combo Product Development

New policies aim to simplify testing for single-pill combos and products that combine drugs with medical devices.

In January, the Food and Drug Administration made headlines by quickly approving a fixed-dose-combination (FDC) treatment for AIDS under a new policy that allows its use in developing nations. Pharma manu-facturers also are building commercial markets at home for FDCs that offer clinical benefit and/or reduced risk.

FDA is encouraging combo product development by modifying preclinical and clinical testing requirements, and clarifying manufacturing standards for new combinations of existing as well as new products. Pharma companies eye combination drugs as a way to both address multiple health needs and simplify treatment regimens. Health plans and insurers appear receptive to paying a premium for products that offer less risk and more convenience, but sponsors have to document long-term benefits in terms of savings and enhanced health.

Focus on FDCs
Pharma companies are enthusiastic about transforming many established drugs for asthma, diabetes, hypertension, and infectious diseases into combination products. These may enhance patient compliance, not just through simplified treatment regimens but also by reducing toxicity and side effects, or boosting drug levels and increasing efficacy. Last year, Pfizer introduced Caduet, which combined Norvasc (amlodipine besylate) for high blood pressure and Lipitor (atrovastatin calcium) for high cholesterol. Previous patient use of the drugs allowed use of existing preclinical and clinical studies to support the combo.

Combination drug products have been around for decades, but until recently were saddled with a negative image in the medical community. Physicians objected that combination pills limited their ability to prescribe specific doses and therapeutic regimens to fit individual patients. Now the medical community is regarding FDCs as products that may offer compliance and safety advantages. A single pill can cut prescribing errors by physicians as well as dispensing mistakes by pharmacists and health care professionals.

Combating AIDS
The antiviral FDC that FDA approved in January was the first AIDS combination product developed specifically for use in third-world nations (see sidebar). Prior to that, FDA had approved new combination therapies for AIDS that may be marketed in the United States as well as in the developing world. GlaxoSmithKline's Epzicom combines 600 mg of abacavir (Ziagen) and 300 mg of lamivudine (Epivir). As the two component drugs were already on the market, FDA approval last August (2004) was based on a well-controlled clinical study showing that using abacavir only once a day had similar antiviral effect as its previous twice-daily dosage when taken with other antiretrovirals.

FDA also approved Gilead Sciences' AIDS treatment Truvada in August after only a four-month review. The product combines 300 mg of Viread (tenofovir) and 200 mg of Emtriva (emtricitabine) into a once-daily dose. Gilead had to conduct bioequivalence studies to demonstrate therapeutic equivalence between the combination drug and the individual products, but benefited from reduced clinical testing requirements. Building on this, in December Gilead and Bristol-Myers Squibb announced plans to develop an FDC combining Truvada and BMS' Sustiva (efavirenz) to create a more potent once-daily treatment.

These products were being tested before FDA published a draft guidance in May that describes a streamlined process for developing and gaining agency approval of combination drugs to treat AIDS, as well as malaria and tuberculosis.¹ In this document, FDA explains that it normally requires sponsors of FDCs to conduct clinical trials to demonstrate that a combination pill is more effective than each component used separately. In treating AIDS, though, FDA acknowledges that such clinical trials are unethical because they would involve exposing infected individuals to suboptimal drug regimens.

Sponsors of new combination products utilizing already approved AIDS therapies thus may only have to submit data from bioavailability/bioequivalence and drug-drug interaction studies. Manufacturers also must demonstrate appropriate manufacturing process controls and product stability, and that in vivo interactions between active ingredients and excipients do not alter a product's pharmacokinetic profile.

FDA aims to streamline testing requirements to further encourage innovative drug combo development. Another new draft guidance describes how less extensive preclinical safety testing may be sufficient for new FDCs and co-packaged versions of already approved drugs, and even for combinations of an approved and a new drug.² If existing toxicological and pharmacokinetic information shows no evidence to suggest possible harmful interaction from the combined product, FDA may allow the sponsor to begin Phase I clinical studies without first completing extensive animal tests.

Bridging studies may suffice for new-old combinations, particularly if the old drug has known safety problems. FDA urges manufacturers to consult with the appropriate drug review division about any specific testing protocol; one objective of the guidance is to establish more uniform standards for reduced preclinical testing across all new drug review divisions.

Complex combos
FDA also is clarifying its policies for developing and bringing to market the growing number of products made of separate components, such as drugs and medical devices, that normally are regulated by separate FDA centers. FDA established the Office of Combination Products (OCP) in late 2002 to deal with the tricky jurisdictional issues related to approving applications for a growing number of advanced diagnostics and drug delivery devices.

Last May, FDA issued a proposed regulation on how OCP will determine a product's "primary mode of action" and, consequently, which FDA center will have primary jurisdiction over the product. Another draft guidance describes procedures for a sponsor to dispute a product assignment decision and clarifies how the agency will levy user fees for combos. And a September FDA draft guidance addresses good manufacturing practices for combination products as part of the agency's broader GMP modernization initiative.³

OCP plans to issue further guidances on how sponsors should report adverse events and handle postapproval changes. Another thorny issue involves cross-labeling for combos developed and manufactured separately. OCP is seeking public comment on this and will hold a public meeting this spring.

Despite these efforts, at a January 2005 summit sponsored by the Regulatory Affairs Professionals Society, sponsors continued to urge FDA to develop a more consistent approach for reviewing combination products. An initial proposal is for FDA to develop a common set of terms and definitions related to combos, starting with "combination product" itself.

Crackdown on conflicts of interest
A new rule from the Department of Health and Human Services will make it more difficult for pharma companies and commercial research organizations to tap the experience of government scientists. In the wake of ethics issues raised primarily at the National Institutes of Health this past year, HHS is requiring FDA to revive a policy requiring employees to file annual statements on financial interests and outside activities involving all regulated companies--not just those with approved products. NIH is restricting staff consulting activities with industry, hospitals, insurers, and health care providers; requiring top staffers to sell any stock in pharma and biotech companies; and to refuse prizes that carry significant awards.

This emphasis on ethics also is boosting an "open access" to NIH research campaign. A separate NIH policy urges agency-funded researchers to post scientific journal articles on an NIH Web site within 12 months of publication. The final policy stops short of mandating public disclosure of scientific information and delays the recommended posting date from six to 12 months. Publishers still fear the public access policy will curb subscriptions, and researchers may face pressure to disclose results earlier.

References
1. www.fda.cder/guidance/6283drft.doc
2. www.fda.gov//cder/guidance/5629dft.pdf
3. www.fda.gov/oc/combination

FDA Retains Control over Drug Safety Monitoring
Health and Human Services Secretary Mike Leavitt unveiled the Drug Safety Oversight Board and the Drug Watch Web site to create a "new culture of openness and enhanced independence" at FDA.

The Drug Safety Oversight Board will be comprised of experts from FDA, HHS, and other agencies. They will recommend disclosures about drug safety information. The panel will be appointed by the FDA commissioner, but housed within the Center for Drug Evaluation and Research, which some consider tantamount to letting the fox keep track of the hen house. The board also will resolve internal disagreements, assess the need for high-risk drugs to carry MedGuides, and weigh the need for additional safety information for professionals and patients.

One of the board's main tasks will be to identify information that should be posted on the Drug Watch Web site. The site will release drug safety information to patients and doctors. This would allow the health care community to learn about drug safety long before the resolution of often lengthy negotiations between FDA and manufacturers over the need for labeling changes.

FDA also said it would be announcing further expansion of its Adverse Event Reporting System (AERS). Next year's FDA budget seeks resources to upgrade AERS to ease electronic filing, and to collect data from agencies both in and out of government.

It was no surprise that these announcements came the day before a meeting to discuss safety issues related to COX-2s. The agency's advisory committees on arthritis and drug safety and risk management voted to keep the COX-2s on the market, but recommended black box warnings and other limitations. Such labeling changes virtually rule out broadcast consumer advertising for these products. Prescriptions of these therapies is expected to remain low.

The decline of COX-2s may by offset by increased reliance on other anti-inflammatories. Evidence indicates that previous hints of increased cardiovascular events with Naproxen (Bayer's Aleve) were blown out of proportion. Testimony from arthritis sufferers bolstered benefit claims, but the panel advised all prescribers to use lowest possible doses. FDA staffers cited the need for a study of 50,000 patients over several years to compare effectiveness of painkillers. It is not clear who would pay for such a trial.

No More Acting: Lester Crawford Is Named as New FDA Commissioner
Naming Acting Commissioner Lester Crawford as head of the Food and Drug Administration was a relatively easy task for the Bush administration. The nomination was a just reward for Crawford's four years of service as acting and deputy FDA commissioner during the first Bush term.

Pharmaceutical manufacturers supported the nomination, pleased at filling the void of unconfirmed FDA leadership. Crawford has been supportive of new drug development initiatives and efficient application approval processes, and is not likely to shake up the agency. He also has no ties to drug companies, a main requirement for Senate Democrats. A veterinarian with a doctorate in pharmacology, Crawford lacks the MD held by most of his predecessors.

Crawford's appointment last month did raise some protests. Public-interest groups complained that he has been slow to respond to safety issues of painkillers, antidepressants, and dietary supplements. FDA's allegedly political delay in approving the morning-after pill, Plan B, remains a bone of contention. Senate Republicans promised speedy confirmation hearings, which will be lively because Crawford cannot claim that he is new to Washington to avoid answering tough questions on drug safety.

Reducing the Number of Adverse Events Filed with IRBs
FDA is holding a public hearing on March 21 to examine whether investigators should send reports to IRBs of all adverse events related to a clinical study. Current policy requires researchers to report all "unanticipated problems." Unfortunately, this means some IRBs receive thousands of reports, many of them unclear and incomplete.

Last July (2004), Ernest Prentice, Chair of the HHS Secretary's Advisory Committee on Human Research Protections (SACHRP), outlined this problem in a letter to HHS secretary Tommy Thompson. Prentice noted that some IRBs received more than 12,000 adverse event reports per year, with considerable variation among them. The proliferation of multicenter trials aggravates the situation because sponsors have to notify all participating investigators, and those investigators, in turn, notify their IRBs.

At its hearing, FDA wants suggestions for improving the process. FDA primarily wants to know what AE data is useful for IRBs and what is the best process for reporting. Should IRBs receive information only about serious and unexpected events? Should the criteria differ for multisite studies? Should investigators or sponsors consolidate and analyze AE reports before submitting them?

FDA also wants to know if AE reporting policies should be the same for drugs and medical devices. Similarly, an HHS task force seeks to harmonize the varied AE policies among HHS agencies. A new HHS guidance proposes that FDA and other organizations adopt similar reporting requirements for all studies, both in the United States and abroad. Comments are due April 21.