Bottleneckrophobia

Thanks to serious international efforts and multiple years of funding from foundations like the Bill and Melinda Gates Foundation and US and European governments, the pipeline of new drugs and drug combinations to treat the big three infectious diseases (HIV/AIDS, tuberculosis, and malaria) is starting to pump out products.  As pointed out by researchers at Policy Cures, a non-profit consulting group in Sidney, Australia, the good news is that there are 20 or so new drugs for diseases of the developing world that have been or are in the process of being approved by several regulatory authorities (Moran et al. 2011).  The less than good news is that the national regulatory authorities (NRAs) in many of the countries where the drugs are intended for use (such as in Africa, the authors’ focus) are not sufficiently staffed and trained to render rapid approvals.  In the past the NRAs have relied on the approval process of the “stringent” authorities of the world, e.g., the US FDA and the European Medicines Agency, but this route has resulted in drugs being approved but not tested in the countries in need or being withdrawn based on first world risk/benefit ratios.  While this bottleneck is clearly a problem for the several non-profit drug developers, e.g., Medicines for Malaria Venture and the Drugs for Neglected Diseases Initiative, it is a strong disincentive for most for-profit developers, excepting the few multinational pharmas with deep pockets and vision, like Sanofi and GlaxoSmithKline.  To my (naïve) way of thinking, a clear path to approval and registration of new drugs (and vaccines, devices, and diagnostics) in the countries of need is required (along with patient investment and vision) for the many mid-sized, and maybe even small, companies to risk a try at developing new, affordable drugs for the neglected diseases.

Harmonization and coordination of drug approval processes is not a new problem, of course, and there has been a substantial effort, focused mainly in the major market, and more recently, emerging market, countries.  As noted recently by PharmaManufacturing.com (MPC article), the International Conference on Harmonization of Technical Requirements for Registration of Pharmaceuticals for Human Use (ICH) and a working group of the US Pharmacopeia (USP), both which started 20 years ago, have achieved good progress on certain aspects of standardization like testing protocols and documentation, mostly in the past five years.  The challenge is large though; another group, the Pan American Network for Drug Regulatory Harmonization, has more than a dozen working groups including those on bioequivalence (to approve “follow-on” or generic drugs), counterfeiting, good clinical practices, good laboratory practices, good manufacturing practices, promotion, biotechnology products, and vaccines (PANDRH).   The MPC article also notes the cost of non-harmony is high; multiple regulatory filings and plant inspections can comprise tens of millions of dollars per product.

One approach to supplementing (or more politically problematic, supplanting) the country-by-country approval process would be an international approval agency.  A possible model for such an agency is the WHO’s Prequalification of Medicines Programme (PQP).  Begun in 2001, the program reviews medicines for treating HIV/AIDS, tuberculosis, malaria, and more recently for reproductive health for eligibility for purchase by international procurement agencies like UNICEF.  These purchases are made by the countries of need, are often subsidized by donors (governments and foundations), and run into billions of dollars per year (PQP Fact Sheet).  Although the PQP has approved 240 products, is low cost (free to applicants thanks to about $10 million per year given by UNITAID; see UNITAID Programs), and strengthens NRAs through a training program, it is slow (two-year average for approvals according to Moran et al.) and only evaluates generic drugs and new combinations and formulations of generics for which there are substantial data and sometimes stringent NRA approvals on the original product.  While the PQP’s approval of such generics is important in making needed treatments accessible and affordable, it would need substantial funding and political will to evolve into a novel drug registration agency.  The WHO also has a similar program to pre-approve vaccines from applicant manufacturers that is slightly different in that it relies on NRAs for initial approval but then requires the NRAs to meet a standard of competence (WHO vaccine program).

As is their wont, Moran et al. offer several alternatives to widen the bottleneck:

  • Include a representative of the endemic country NRA in the deliberations of stringent agency approval of a new neglected disease drug (NDD) [but who is the ultimately responsible party?];
  • Allow a NDD approved by a stringent agency to qualify for WHO prequalification status (this was done for generic HIV/AIDS drugs) [but still means that NDDs may not be reviewed with the appropriate criteria];
  • Use the “Article 58” process of the EU (in which an expert panel renders an “opinion” on the use of a drug outside the EU) but gie those drug developers a shorter path to EU market approval [as an incentive to developers of dual market drugs; but for ND-only drugs?];
  • Strengthen the WHO PQP with help from stringent NRAs or expert panels to allow it to recommend/almost approve new drugs [might work, see below]; and
  • Create regional regulatory agencies responsible for each of Africa’s main regions [sounds too bureaucratic and piecemeal to me].

Overlooked by Moran et al. is the deep expertise, experience, and possible motivation of the for-profit drug developers themselves.  After all, the major and mid-tier pharma companies spend billions of dollars conducting trials by themselves or through contract firms (CROs), more often in countries where costs are low but registration is not expected, and are willing to pay substantial “users’ fees” to the USFDA to make sure the agency does its job (about 60% of the FDA budget or $570 million in 2011 according to a Washington Post business blog, Klein blog).  While having such a financial dependency of a regulating agency on the regulated may not be a good idea, I think there is a concordance of interest between industry and the harmonization efforts of the ICH, USP, and others (like the Bio Supply Management Alliance I mentioned last week) on one hand and the WHO PQP and the NRAs of the rest of the world and given the right framework these groups may cooperate to build a better international registration system, one that provides a path and an incentive for the development and registration of NDDs.  I can see an upgrading of the PQP with regulatory expertise from stringent NRAs and industry to create an alternative path to country-by-country registration with the “qualified” products and manufacturers being eligible for purchase by “qualified” buyers, which would be any government or group able to commit to negotiated volumes and prices.  Another close-to-international registration program for NDDs could result from cooperation between the PANDRH mentioned above and the Pan American Health Organization’s Revolving Fund mentioned in my post, “More Bang for the Buck”.  Clearly, I need to do more research on this idea and get others’ input (policy wonks, speak up), but think it has merit.