Representatives of drug regulatory authorities from southern Africa, Canada, Switzerland, Ghana, Tanzania, India, Indonesia, USA and Thailand have reached agreement on standards for approval of fixed dose antiretroviral combinations following a two-day meeting in Gaborone, Botswana on March 29th and 30th.
Although the standards are not binding, they are likely to influence regulatory authorities in southern Africa and other regions where demand will be high for fixed dose antiretroviral products. They will also be an important tool for advocates seeking to persuade the US administration to purchase generic antiretroviral fixed dose products. The standards also cover potential fixed dose products for treatment of tuberculosis and malaria.
A discussion document that reflects the key decisions from the meeting was published today at the Global Health Council website.
Controversy over US stance on fixed dose combinations
The meeting, convened by the United States government and the Southern African Development Council (SADC) with support from WHO and UNAIDS, had been widely interpreted as a US government attempt to prevent the use of fixed dose combinations (FDCs) of generically manufactured ARVs with money from the Presidential Emergency Plan for AIDS Relief (PEPFAR). The meeting followed a similar event organised last December by the World Health Organisation, as well as a string of US criticisms of the World Health Organisation's prequalification process for antiretrovirals, which allows WHO to review data on a product and indicate that it is properly manufactured and bioequivalent (if a generic product).
However, speaking in the opening session of the meeting, Dr Mark Dybul (deputy chief medical officer in the US Global AIDS Coordinator's office) said: “The US agrees that fixed dose combinations are an important goal, and it is important that there are internationally agreed standards that allow the US to move beyond [the purchase of] FDA-approved drugs.”
“This meeting is not intended to endorse drugs, set up guidelines or to avoid using fixed dose combinations, to avoid using generics, or to set up a higher standard or to subvert the WHO prequalification system,” he went on.
Indeed, the meeting gave little impression of being a US-stage managed event. It was chaired with considerable diplomacy by Precious Matsoso of SADC and with considerable firmness by Lembit Rago of the World Health Organisation, who spelled out WHO’s position on the proceedings in the opening session.
“WHO will not commit itself to support the outcome of this meeting if it stands in the way of providing FDCs to those who need them,” he told delegates. He urged experienced regulators at the meeting to come up with proposals that would allow FDCs to be approved more quickly, without giving rise to undue harm. He also warned that WHO had not come to the meeting to debate the validity of its prequalification procedure, which has been criticised by the US administration as lacking in transparency.
Ellen t’Hoen of Medecins sans Frontieres said at the close of the meeting: “This meeting has shown that an international consensus on how to approve fixed dose combinations exists.”
Pharmaceutical companies
Both branded and generic manufacturers who attended the meeting (Merck, GlaxoSmithKline, Abbott, Roche, Bristol Myers Squibb, Cipla, Ranbaxy/Thembalami and Aspen Pharmacare) appeared, on the surface at least, satisfied with the outcomes of the meeting. Dr Nic de Jongh of Cipla Medpro, the South African division of Cipla, told the meeting: “In all our submissions to regulatory authorities we have followed the principles summarised in this document.”
Branded manufacturers are keen to define a set of standards that will guide regulatory authorities in developing countries. They hope to announce within the next month that they have reached agreement on how to work together to produce blister-packed combinations of each other’s products for use in developing countries, and in the longer term how they plan to develop fixed dose combinations using products from competing companies.
The consensus
The meeting endorsed a four-scenario approach to registration of fixed dose combinations. The key study requirements for each scenario are listed below. Manufacturers will also have to fulfil the same quality and manufacturing standards as for other pharmaceutical products.
Scenario 1: Approval of products that are straightforward copies of existing fixed dose combinations
(e.g. AZT/3TC)
A straightforward bioequivalence study in 24 to 36 individuals will be required, comparing the generic product with the original branded product.
Scenario 2: Products that combine well-studied combinations of drugs into a new fixed dose combination
(e.g. d4T/3TC/nevirapine and all other drug combinations recommended for first line therapy in resource-limited settings, with the possible exception of ritonavir/saquinavir when it is combined with nucleoside analogues)
New clinical efficacy data will not be required. Instead a randomised two-way crossover study with a washout period between arms of at least five times the half life of the product with longest period of activity will be required to prove bioequivalence, and each component in the fixed dose combination must show bioequivalence.
The discussion document issued on April 27th does not clarify a debate that took place during the meeting, which appeared to conclude with the agreement that bioequivalence studies for scenario 1 and 2 product approvals should take place in HIV-negative volunteers.
Scenario 3: Products that combine agents that are well characterised in their own right but which have not been used extensively in combination
(eg ddI/tenofovir/atazanavir, or efavirenz dosed at 800mg for TB patients receiving rifampicin when combined with other products, or efavirenz daily dosing split into two 300mg doses combined with AZT/3TC, or once daily lopinavir/ritonavir). Toxicity and bioequivalence studies will be necessary together with pharmacokinetic and pharmacodynamic studies, plus a clinical efficacy study showing non-inferiority, equivalence or superiority, depending on the nature of the comparator.
Where there is the potential for a drug interaction or overlapping toxicity, preclinical toxicity studies, clinical safety studies and dose ranging studies may be needed before embarking on clinical efficacy studies.
Scenario 4: Combinations that include unlicensed, novel products
(e.g. a new protease inhibitor combined with an existing fixed dose combination of nucleoside analogues).
These would be treated just like any other novel product registration, with all the requirements of such a licensing process.
Next steps
A document summarising the conclusions of the meeting has been released for comment (see link above). Interested parties have until May 10 to submit comments.
Subsequent to the meeting US officials have made no public comment on the fixed dose combination controversy.
Effects of uncertainties over FDCs on the ground
During the meeting, a number of treatment providers warned of the problems that could ensue if donors did not agree on the types of products that could be purchased with their financial support.
Dr Eric Goemaere of MSF’s Khayelitsha project, South Africa, noted that, in the Western Cape, the government has determined that a budget of R60 million is needed to provide ARVs for all who need them. Only R23 million has been identified. Western Cape will have to seek public/private partnerships and funding from bilateral sources. “If each partner comes to us only wanting to treat women or children, or only wanting to use a certain drug combination or branded products, it will be chaos. If we have different supplies and different combinations coming in, it will create confusion both for the clinic and for patients who have already started with a particular FDC.”
Jennifer Patterson, of PEPFAR grant recipient Catholic Relief Services, representing Catholic medical missions already providing generic ARV treatment to `thousands` in Africa and the Caribbean with `well documented positive outcomes`, told the meeting that her affiliates were concerned that current PEPFAR guidelines would force existing programmes using generic FDCs to switch to branded products in order to comply with the recent PEPFAR grant. “Our programmes fear that they will suffer the burden of administration of multiple supply lines, that community workers will face the extra burden of explaining different regimens to patients within the same family, and that the use of loose tablets rather than FDCs will create the danger of pill-sharing between family members because of the prevailing sense of community.”
Note
Keith Alcorn attended the March 29-30 meeting as an observer on behalf of the United Kingdom Department for International Development.