Download BASICS OF DRUG REGISTRATION

BASICS OF DRUG REGISTRATION
Prof. Brook K. Baker
Background - originator drug registration: Drug registration for products not previously
granted marketing approval is usually granted through one of two processes. In the first process,
the drug regulatory authority examines voluminous pre-clinical and clinical data (animal studies,
toxicity studies, stability studies, Phase I, II, and III clinical trials, and specification of
manufacturing process) to ascertain the safety, efficacy, and quality of the pharmaceutical
product. This is the process followed by the FDA and most stringent regulatory authorities.
Preparing these complex registration applications/dossiers is expensive and time-consuming, and
requirements can and do vary from country to country, adding the expense of multiple filings.
Moreover, processing this complex data within the drug regulatory authority is also timeconsuming, even in the U.S., and can often take many months or even years to complete.
In the second process, rather than reviewing all the underlying data, the drug regulatory
authority relies on the fact of registration elsewhere to establish the safety, efficacy, and quality
of the product. Here, the registration application is much simpler and more straight-forward. The
registrant essentially files a limited application and a certificate confirming the fact of registration
by an "approved" foreign drug regulatory authority and evidence of Good Manufacturing Practice
(GMP). The second drug regulatory authority can thereafter quickly register the new product
because it does not have to review underlying data. A variation of this process is when the drug
registration authorities examine a limited set of published studies or product specifications, i.e.
Pharmacopeias, to determine product safety, efficacy, and quality.
Background - registration of a follow-on product: Just as there are two processes for
registering an originator product, there are two basic abbreviated processes for registering followon generic equivalents. In the first process, the drug regulatory authority actually references or
reviews the originator's data to confirm that the follow-on product is therapeutically equivalent
and thus entitled to expedited registration without the full panoply of clinical trial data. In most
countries, the follow-on registrant merely provides evidence of bio-equivalence (or a lesser
standard of therapeutic similarity) between the originator and the follow-on product, and separate
evidence of the product's quality (usually via evidence that it was produced pursuant to GMP).
Thereafter, the drug regulatory authority reviews that limited evidence and via reference to the
originator’s underlying data assesses whether the follow-on product is therapeutically equivalent
and of good quality or not.
In the second follow-on process, the drug regulatory authority does not actually reference
or examine the originator's data, it simply relies on the fact of the originator product’s registration
to determine whether or not to register a therapeutically equivalent follow-on products. The
follow-on producer ordinarily submits the same kind of evidence of bio-equivalence (or
similarity) and GMP as it would in the first follow-on process.
Background – fast track registration: In addition to these basic variations, some
countries have also adopted “fast-track” procedures for the registration of priority medicines.
This has resulted from pressure both by producers of pharmaceutical products who want to
shorten the period of regulatory delay and by consumers who want expedited or special access to
medicines for currently incurable conditions. Priority can be established by moving applications
to the front of the line, by devoting more human resources, or by applying simplified standards.
Background – WHO: The WHO set up a comprehensive system of trying to regulate
procedures for certifying the safety and efficacy and GMP of pharmaceutical products moving in
international commerce as a way of facilitating registration of medicines in developing countries.1
The WHO Certification Scheme attempted to provide quality assurance for imported medicines
by means of standard forms confirming the registration of the product in the country of
1
See WHO, USE OF THE WHO CERTIFICATION SCHEME ON THE QUALITY OF PHARMACEUTICAL PRODUCTS MOVING IN
INTERNATIONAL COMMERCE (1995), available at http://whqlibdoc.who.int/hq/1994/WHO_DAP_94.21.pdf
manufacture (Certificate of Pharmaceutical Product), approval of GMP manufacturing conditions
based on inspections, and quality analysis of the product. Based on these assurances, developing
countries were expected to be able to promptly register and/or procure products of assured
quality. Even after 20 years of the existence, the WHO Certification Scheme is not being widely
used.
In 2001, the WHO established its Prequalification Programme to provide UN
procurement agencies and other procurers with a reliable, non-regulatory mechanism for ensuring
the safety, efficacy, and quality of medicines used to treat HIV/AIDS, tuberculosis, and malaria.2
The Prequalification Programme requires manufacturers who wish to be listed to provide a
product dossier including details about the finished product, the purity of ingredients, stability
studies, and in vivo bioequivalence studies. After an initial assessment, the product is sent for
testing by stringent laboratories and manufacturing sites are inspected for compliance with WHO
GMP. Only then is the product added to the list of WHO prequalified drugs. As of January 4,
2008, WHO had prequalified 171 HIV/AIDS medicines.3
From the prospect of access to medicines, the global and national architecture for
registering medicines is already extraordinarily complex and fraught with inefficiencies,
duplications, delay,4 and in some instances corruption.5 Registration-related problems arise
because of mismatches in economic incentives for both innovator and generic producers, and
2
WHO, KEY FACTS ABOUT PREQUALIFICATION PROGRAMME (2006), available at
http://mednet3.who.int/prequal/prequal_keyfacts.htm.
3
WHO LIST OF PREQUALIFIED MEDICINES (2008), http://healthtech.who.int/pq/status/ProductRegistry.aspx?list=ha.
4 WHO, THE WORLD MEDICINES SITUATION 93-112 (2004), available at
http://www.who.int/medicinedocs/collect/medicinedocs/pdf/s6160e/s6160e.pdf; WHO, WHO MEDICINES STRATEGY:
COUNTRIES AT THE CORE 94-110 (2004), available at http://whqlibdoc.who.int/hq/2004/WHO_EDM_2004.5.pdf.
5 WHO, MEASURING TRANSPARENCY IN MEDICINES REGISTRATION, SELECTION AND PROCUREMENT: FOUR COUNTRY
ASSESSMENT STUDIES, 1 (2006), available at
http://www.who.int/medicines/areas/policy/goodgovernance/Transparency4CountryStudy.pdf. The combination of
inefficiency, incapacity, and corruption has resulted in a very high proportion of sub-standard and counterfeit drugs on
the market in developing countries. WHO, “Substandard and Counterfeit Medicines” Fact sheet No. 275 (2003)
(estimating that up to 25% of drugs consumed in developing countries are counterfeit or substandard), available at
http://www/who/int/mediacentre/factsheets/2003/fs275/en/. In 2006, the WHO set up a special task force on drug
counterfeiting. John Zarocostas, WHO to set up international task force on counterfeit drugs, 332 BRIT. MED. J. 444
(2006).
because of regulatory torpor and unaccountability at the national and international level.
Registration-related barriers include:
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Lack of incentive mechanisms or regulatory systems that compel innovator companies to
promptly register their medicines for use in smaller and poorer countries with resulting
excessive delay in access to newer medicines;6
Lack of sufficient incentive mechanisms, technical assistance, or other measures to
encourage generic companies to promptly register their therapeutic equivalents for use in
smaller and poorer countries;
Absence of fast-track registration procedures in most countries designed to expedite
registration of medicines that have been accepted by the WHO Prequalification Project or
registered by a stringent regulatory authority in another country;7
Absence of efficient special authorization procedures that allow emergency access to
important medicines while the formal registration process is being completed.8
Lack of capacity, inefficiency, high costs,9 regulatory variations,10 and occasional
corruption in national drug regulatory authorities that create delays and disincentives to
both innovators and producers of generic equivalents;
Insufficient capacity and delays in the WHO prequalification system that result in
delayed registration of newer medicines;
Duplication of effort by the United States Food and Drug Administration (FDA) and the
“fast-track” tentative approval system required by the President’s Emergency Plan for
AIDS Relief (PEPFAR), which does not allow purchase of medicines accepted by the
WHO Prequalification Programme;
Lack of post-approval quality assurance mechanisms and lack of efficient supervision of
the marketing of medicine to prevent the use of substandard or counterfeit medicines;
Lack of a global, up-to-date, accessible registry on registration status of HIV/AIDS
medicines.
There are numerous important AIDS medicines that are still not registered in many developing countries, including
atazanavir, tenofovir, emtricitabine, lopinavir, ritnavir, and Atripla. Brook K. Baker, Drug Registration Barriers &
Logjams in MISSING THE TARGET #5: IMPROVING AIDS DRUG ACCESS AND ADVANCING HEALTH CARE FOR ALL, 50-52
(2007), available at http://www.aidstreatmentaccess.org/itpc5th.pdf. On the plus side, a separate study by the WHO
found that the vast majority of ARVs in use in sub-Saharan Africa were registered and of good quality. WHO, SURVEY
OF THE QUALITY OF ANTIRETROVIRAL MEDICINES CIRCULATING IN SELECTED AFRICA COUNTRIES (2007), available at
http://www.who.int/medicines/publications/ARV_survey.pdf.
7 Id. at 53-54.
8 See WHO, CERTIFICATION SCHEME supra note 38.
9 The typical registration fee in the United States is $500,000 to which one must add attorney’s fees and dossier
preparation costs; registration fees in developing countries are ordinarily much cheaper, ranging from $100 in Malaysia
to $4300 in South Africa.
10 There are substantial costs arising from differing requirements for registration dossiers, attorney’s fees, and
translation costs. These costs are problematic even in rich country markets. See E.C., BETTER REGULATION OF
PHARMACEUTICALS: TOWARDS A SIMPLER, CLEARER AND MORE FLEXIBLE FRAMEWORK ON VARIATIONS (Oct. 20, 2006),
available at
http://ec.europa.eu/enterprise/pharmaceuticals/varreg/variations_consultation_paper_codecision_20070710.pdf .