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Ensuring access to quality medicines while ramping up production requires attention to supply chains, bioequivalence testing, and patent and regulatory issues.
With millions of impoverished people suffering from AIDS, tuberculosis, malaria, and other deadly diseases, the pharmaceutical industry faces unprecedented demands for safe and effective life-saving treatments. US, European, and international organizations are pledging billions to treat some five million AIDS patients, primarily in sub-Saharan Africa, in the next few years. The situation presents a challenge and an opportunity for pharmaceutical manufacturers to demonstrate their ability to provide affordable, effective treatments to fight these global plagues.
This effort involves an enormous scale-up in pharmaceutical manufacturing capacity without compromising product quality. Soaring demand for antiretroviral medicines (ARVs) and artemisinin-based antimalarials is creating raw material shortages and stressing pharmaceutical distribution and supply chain operations (see sidebar, "Growing antimalarial ingredients"). These activities raise the threat of drug diversion from third-world markets to rich nations and open the door to unscrupulous counterfeiters. Pharmaceutical companies are responding by negotiating licensing arrangements with generics firms to produce low-cost products while also expanding individual assistance programs (see sidebar, "Push for diagnostics"). At the same time, health agencies and regulators are devising new strategies to overcome legal and political hurdles to generate needed medical products.
Growing antimalarial ingredients
Supplying ARVs, particularly the fixed-dose combination (FDC) drugs found most effective in AIDS treatment, to meet these goals requires a major expansion in drug manufacturing operations, along with innovation in product formulation and manufacturing technology. But developing effective combination products, meeting worldwide regulatory standards, and producing ingredients are serious challenges. Bristol-Myers Squibb, for example, reported in March 2005 that it had problems meeting demand for "Zerit" (stavudine) and "Sustiva" (efavirenz).
Push for diagnostics
International health agencies seek to spur development of additional FDC drugs to provide simpler drug regimens consisting of one or two pills per day. FDC drugs have not been readily available in the United States, largely because brand-name manufacturers have not been very interested in co-developing products composed of drugs from various companies. In addition, US physicians prefer to prescribe drug "cocktails" to fit the medical needs of individual patients instead of using preformulated combination products.
This lack of interest among innovator firms opened the door for Indian generic drug makers to formulate safe and effective FDC drugs. The World Health Organization (WHO) supported this effort by establishing a prequalification program in 2001 to confirm the safety and quality of medicines for malaria, tuberculosis, and HIV/AIDS. The WHO program aims to assure health agencies in developing nations, which often have limited internal drug evaluation capabilities, that products on its prequalification list meet predetermined criteria for safety, efficacy, and manufacturing quality. WHO relies primarily on manufacturer data to document safety and bioequivalence, but also can analyze drug samples and visit manufacturing and laboratory sites to ensure compliance with international standards for manufacturing (good manufacturing practices [GMPs]) and for clinical and laboratory testing (good laboratory practices [GLPs] and good clinical practices [GCPs]).
The prequalification program ran into trouble this past year, putting pressure on ARV suppliers, when discrepancies in bioequivalency reports forced WHO to remove a number of antivirals from its list. WHO pulled several Ranbaxy products in August 2004, followed by additional drugs from Ranbaxy and Hetero Drugs, another Indian manufacturer, because the laboratories used by these manufacturers for bioequivalency testing did not meet GCP/GLP standards, and some manufacturer bioequivalency data did not match information submitted in applications. WHO discovered these problems after it began conducting its own inspections of contract research organizations and laboratories doing bioequivalency tests, prompted by a European Union (EU) directive that went into effect in May 2004 requiring EU member countries to have manufacturers monitor test laboratories more closely. It has taken Ranbaxy a year to requalify all its AIDS drugs for the WHO list.
The bioequivalency data problems raised questions about the reliability of WHO's prequalification approach, a skepticism shared by US health officials. Even though WHO officials claimed that its delisting action confirms its high standards, the US President's Emergency Plan for AIDS Relief (PEPFAR), which plans to spend $15 billion over five years to provide treatment to two million HIV-infected people (up from its current spending of approximately $250,000), says that drugs purchased with US dollars must be approved by the US Food and Drug Administration, ostensibly to avoid charges that Americans are foisting lower quality treatments on poor nations.
Critics argue that the US position really aims to protect pharmaceutical manufacturers from increased competition from generic FDCs. A program that purchases only FDA-approved products, moreover, means paying more for brand-name drugs and, consequently, limiting the number of patients the program can treat. The US refusal to purchase WHO-approved drugs also creates logistics problems because local clinics and hospitals must segregate those drugs purchased with US funds from others.
To get around these problems, FDA is granting tentative approval to generic drugs that meet regulatory standards. These products consequently are eligible for purchase by PEPFAR programs but cannot come to market in the United States because of patent restraints. An FDA guidance published in May 2004 spells out how manufacturers can develop and gain expedited review of fixed-dose combination and co-packaged versions of ARVs (see Pharm. Technol., Washington Report, July 2004).
Although many observers still regard the FDA approach as a waste of money and resources, the prospect of qualifying for purchase by PEPFAR is attracting applicants, and the accelerated review policy has helped bring new AIDS therapies to market quickly. In August 2004, GlaxoSmithKline announced accelerated approval of a new combination drug "Epzicom," composed of the company's "Ziagen" (abacavir) and "Epivir" (lamivudine). FDA also approved Gilead Sciences' "Truvada," which combines "Viread" (tenofovir) and "Emtriva" (emtricitabine) into a once-daily dose. Barr Laboratories similarly gained a faster approval in December 2004 for didanoside delayed-release capsules, a generic version of BMS's "Videx."
This year FDA has granted generics firms tentative approval for several AIDS therapies, and a dozen applications are in the review pipeline. The first came in January 2005 for a co-packaged generic antiretroviral drug regimen manufactured by Aspen Pharmacare of South Africa, which has emerged as a major generic drug producer for AIDS programs throughout Africa. The Aspen product includes two tablets each of generic versions of Glaxo's FDC drug "Combivir" (lamivudine/zidovudine) and Boehringer's "Viramune" (nevirapine), each to be taken twice daily. Another FDC drug gained tentative approval in July—a generic version of Combivir from India's Aurobindo Pharma. Aurobindo and Ranbaxy Laboratories also gained tentative approval for several leading individual AIDS treatments, including lamivudine, zidovudine, nevirapine, efavirenz, and stavudine.
FDA has approved PEPFAR applications in four to eight weeks, says Murray Lumpkin, FDA deputy commissioner in charge of international and AIDS programs, largely because its Office of Generic Drugs (OGD) is helping manufacturers design appropriate test programs and prepare applications correctly, assistance that is especially important for companies such as Aspen that were unfamiliar with FDA procedures. Speedy approvals require quality applications and early inspection of bioequivalence data and manufacturing facilities, Lumpkin explains.
Although FDA approval makes these generic products eligible for purchase by PEPFAR, manufacturers must register the drugs in each recipient country before they can be distributed to patients. A number of African governments also want FDA-approved drugs included on WHO's prequalification list so that they can use the same drugs for all programs. FDA and WHO officials recently signed an agreement to share confidential regulatory information, which will make it easier for WHO to access FDA data to quickly add any new drugs to its prequalification list. Manufacturers usually agree to any FDA requests to share trade secret data about drug formulation and manufacturing process with agencies such as WHO.
Not all FDCs are easy to formulate, however. This past December, Gilead and Bristol-Myers Squibb announced plans to develop a new FDC drug combining Truvada and Sustiva to create a more potent once-daily AIDS treatment. The companies acknowledged in August, though, that several test versions of the new combination drug failed to achieve bioequivalence to the drugs used separately. Gilead said that it planned to test three additional formulations in hopes of submitting an application in 2006.
As with WHO's prequalification program, problems with bioequivalence testing are the main reason for FDA to reject applications for new FDCs. A related issue is whether generics firms must use a US-approved drug as the reference product when seeking tentative approval of an AIDS therapy that will be used only overseas. A US reference drug is required for generic drugs intended to be marketed in the United States, but FDA may allow flexibility for drugs seeking only tentative approval.
To help manufacturers around the world meet quality standards in developing new versions of drugs to treat AIDS and malaria, the US Pharmacopeia (USP) is proposing to develop "flexible" monographs about drugs that may adopt alternative synthetic routes and alternate formulations not widely used in the United States. This USP Global Assistance initiative would help other countries develop monographs on local products, which could reduce production of substandard and counterfeit drugs.
Managing the supply chain
Manufacturers recognize that drug counterfeiting and illegal diversion of low-cost FDCs from third-world markets is likely to rise along with increased demand for AIDS therapies. The United Kingdom's National Health Service reported in April that it had erroneously purchased ARVs that were illegally diverted from Kenya. The Global Fund to Fight AIDS, Tuberculosis, and Malaria recently halted its AIDS programs in Uganda after audits uncovered discrepancies in program accounts. Nigeria's AIDS program acknowledged difficulties a year ago providing ARVs to patients due to corruption leading to drug shortages.
To prevent such debacles, PEPFAR and other donor agencies are developing secure and efficient distribution and warehousing systems to manage the fast-expanding quantities of ARVs exported to developing countries. PEPFAR is supporting an initiative by the US Agency for International Development (USAID) to establish its own secure supply chain management system (SCMS) to procure pharmaceuticals and other needed products for the program's 15 focus countries. The contract, which could amount to $7 billion during a five year period, has been in the works for months and aims to provide a "one-stop shopping point" for medical supplies used by all similar healthcare programs. Among its broad responsibilities, the contractor is supposed to prevent theft, deterioration and diversion of field supplies, as well as test drug shipments to verify that product lots meet specifications and follow storage and handling requirements.
Many observers consider the PEPFAR/USAID program unnecessary and redundant with efforts to build secure supply chain systems for medical products already under development by the Global Fund, WHO, and recipient countries. PEPFAR officials say that local governments and third-party donor programs will have the option of using the SCMS system, but organizations receiving PEPFAR funds may well feel pressure to adopt the US program, even though it may prove wasteful and counterproductive.
Although the immediate goal of donor organizations and AIDS programs is to provide treatment for millions of infected patients, a broader aim is to encourage development of new therapies, formulations, and production methods to meet demand. The good news is that pressure to reduce prices and cede patent rights does not seem to be curbing innovation.
In July, Boehringer Ingelheim announced FDA approval of its new protease inhibitor "Aptivus" (tipranavir) to be used in combination with Abbott Laboratory's "Norvir." Massachusetts-based Panacos Pharmaceuticals announced early clinical trial results in August indicating high efficacy from a new maturation inhibitor antiretroviral made from the bark of the European plane tree. New studies are examining whether ARVs may be effective at preventing HIV infection in the first place. Research also is generating hope for new medicines to treat malaria and tuberculosis. This past year, the Institute of Medicine issued a report calling for major global investment in new artemisinin-based combination malaria treatments because of the drug's positive results. Promising new treatments against tuberculosis are being tested, which is important in the United States as drug-resistant tuberculosis cases emerge in California and elsewhere. The resulting new treatments may further prevent the spread of deadly disease and help cure already stricken patients.
Jill Wechsler is Pharmaceutical Technology's Washington editor, 7715 Rocton Ave., Chevy Chase, MD 20815, tel. 301.656.4634, firstname.lastname@example.org