World Health Organization Prequalification Program

The first Model List of Essential Medicine popularly referred to as the Essential
Medicines List (EML) was published by the World Health Organization (WHO) in 1977. This
list was instrumental to the authorities as it helped in the selection of primary health care
products. It came up with the notion that there were medicines that were more important
compared to others. This was regarded by many as a paradigm shift in public health. In 2001,
WHO passed an important decision meant at prequalifying medicines (1). According to Worku
and Gordon et al (2) WHO Prequalification of Medicines Program (PQP)’s greatest success is
attaining better-quality lifesaving drugs that are currently in use by low- and middle-income
countries and has positively impacted millions of people. This article focuses on the historical
background the program, its development, what it has achieved and some challenging areas it is
facing.
Effective treatment is safeguarded by the quality of medicines. In addition, it can also
boost a patient’s assurance about the treatment while helping in the prevention of growth of
resistance. This challenges are widespread in countries with weak regulatory oversight which
makes up about a third low and middle income countries where the price of medicines makes
them inaccessible to patients who need them most and where the normal supply chains do not
reach where they are needed most due to weak systems such as poor infrastructure, political
instability and more(2).
From the WHO website, the PQP was started in 2001 with the aim of improving access to
medicines that were compliant in terms of quality, safety in addition to effectiveness for
tuberculosis, malaria and HIV/AIDS. The supporters of the program included World Bank,
UNAIDS, UNICEF and UNFPA(4).

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Global Health Environment

National government and donors did not emphasize on quality assurance when it came to
essential medicines. WHO argued that only a third of the regulatory agencies met the quality
threshold. They continued by stating that the rest, which makes up of two thirds did not have
adequate resources, lacked procedures in addition to the capacity to enforce(5). Medecins Sans
Frontieres (MSF) and UNICEF’s International Dispensary Association (IDA) had solid supply
chains and quality assurance mechanisms which were used by WHO and a number of bilateral
donors.
Only one person among a thousand people living with HIV/AIDS in Africa had access to
treatment in the year 2000. At the same time, high quality ARV medicine were available in
wealthy countries. In the wealthy countries, AIDS moved from being a death sentence to a
chronic disease that is manageable. The drugs were only available from their mother companies
who had full patent control. They kept production low which created a huge demand for the
drugs thus attracting high price tags that were over USD 10,000 for one individual per year(6).
People joined forces through civil societies and health workers professionals
campaigning for better access when it came to HIV treatment, resource allocation and leniency
when it came to patent rules that had crippled the production of the life saving drugs. This was
followed by controversies in relation to ARV patents with new international and more stringent
laws relating to intellectual property. These patents crippled organizations such as UNICEF,
MSF and IDA from supporting and distributing generic ARVs produced in India(6).
In the global arena, most producers did not believe that Indian drug regulatory authorities
had the capacity to validate the quality of the medicine produced in the country. India on the
other hand is a global leader in the production of generic medicine that are cheaper, yet effective

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and are used in most developing countries globally. Fixed dose combinations (FDCs) of ARVs
medication in addition to pediatric ARV formulation coming from India did not have any
originator equivalent. This means that medicine produced and regulated in India was different
from medicine produced on high income countries. This created a regulatory challenge since
both the national and international organizations had no capacity to guarantee quality since the
systems, they had in place were limited in relation to scope. Member states for WHO made a
request to the organization to help in procuring organizations through assessing the quality and
effectiveness of increasingly available medicine that were generic in nature(7).
This role was suitable for WHO since its core mandate was to set out global
pharmaceutical standards. At the start, the organization main focus was on cheap generic
medicines for malaria, TB, and HIV. Over the years, the program has transformed and grown
with its mandate aiming at improving safe and effective medicine availability. This is to be
achieved through covering; essential medications for diarrhea, neglected tropical diseases in
addition to reproductive health, active pharmaceutical ingredients, quality checks laboratories,
generic medicine review and finally building capacity for both pharmaceutical producers and
regulators of medicine in third world and developing countries in both Asia and Africa. The
following figure shows products prequalified by the WHO prequalification program as at
January 2019(8).

Fig 1: Approved Product by WHO prequalification program(8).

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Patent issues

When the World Trade Organization (WTO) was formed in 1995, Trade Related Aspects
of Intellectual Property Rights (TRIPS) was enforced. This is laid down the framework for the
threshold for intellectual property protection that incorporated giving pharmaceutical product
patents that went for a minimum of twenty years. These types of patents were not there in
developing nations. In 2001, a ministerial conference for the WTO aimed at simplifying the
distribution and access of cheap generic medicine discussed how to make the intellectual
property laws related to medicine flexible in developing nations in order to improve access to
better health. The Doha Declaration was implemented as a result(9).
With the Doha Declaration, there was an affirmation that governments reserved the
sovereign right of taking measures on improving and protecting the public health. This was
inclusive of the use of “compulsory licensing and parallel importation”. The compulsory license
gave government the power to give license on the use of patented invention to government
agencies and other third-party stakeholders without requiring to get consent from the holder of
the patent. The entity that is granted the compulsory license however needs to pay a royalty fee
to the patent holder. On the other hand, parallel imports relate to cross border trading on products

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that are patented void of permission from the patent owner, manufacturer or publisher. This take
place when there are great differences related to the price of a similar product in different
markets(2).
Doha Declaration also permitted third world countries not to enforce pharmaceutical
product patents before the year 2016 which brought to an end patent bottlenecks that hindered
importation of generic medicine from India. The implementation deadline was prolonged to July
2021 in 2002. These steps and standards came to be referred to as the TRIPS flexibilities. When
a firm in India known as Cipla in 2001 made an announcement that it would supply ARVs drugs
for less than a dollar a day, it was clear that emerging generic medicines would grow and become
an important factor in improving the access of HIV treatment particularly in developing
nations(10).

Problems leading to the birth of WHO Prequalification

The Global Fund to fight Aids, malaria and TB was established in early 2002 following
its endorsement in the previous year by the G8. It faced numerous challenges when it came to the
effective utilization of funds. Donors and the Fund would require air tight reassurance on quality
and effectiveness when it came to new medicine that were cheap and generic(2). The staff at the
Global Fund were well aware about the risks of spending huge amount of money on medicine
that has not been well tested in terms of quality but cheap or on well established brands that were
expensive and equally effective generic brands were in the market(11).
There was a particularly alarming case related to medications of TB. WHO received
worrying results in 1999 related to a small pilot study in South Africa that had been carried out
by some researchers about the quality of FDCs use as first line treatment of TB. Quality control
tests carried out found the tablets used for treatment to have contained rifampicin, an important

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element of the combination that made the program executives that the tablets were of the right
standards. Further testing however showed that rifampicin in six out of ten samples was not
properly absorbed in the patients’ body thus did not serve their medical purpose(12). If these
results were representative, it showed that almost half of those getting treated for TB with this
particular medication did not receive the most important component in fighting the disease. The
outcome of this would be increased resistance coupled up with poor treatment results. These
results were not put out to the public. They were however passed to the relevant authorities as
confidential matters. WHO was convinced that there were major discrepancies with TB drugs
used in public programs. There was an urgent need to have improved assurance and quality
checks regardless of the fact that most healthcare professionals and donors did not have
knowledge of the underlying problems(2).
FDC AIDS tablets that were produced in India by generic companies, required to undergo
thorough quality assurances test. Most regulators in China, South Africa, India and other drug
generic producing countries were dealing in new grounds since they lacked the experience of
dealing with the fairly new drugs. There was an urgent need for a lasting and quick solutions
since the drug originators were beyond reach to many who needed the drugs in terms of price
point. In India, companies continued to develop FDCs of ARV drugs without regards to patents
that were from various originators. Some of the questions that were in the minds of regulators
included coming up with a way of trusting the new generic drugs from India and establishing
their effectiveness. This led to WHO creating a solid review process that was meant to assess the
standards put in place by regulatory agencies in establishing product quality, safety in addition to
its effectiveness. This led to the formation of WHO Prequalification program. Its approval

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mechanism has since been duplicated by national bodies such as the United States Food and
Drug Administration (US FDA)(13).

WHO Prequalification program Crisis

After an intense debate in the assembly, WHO was faced with information that would
bring damage and raise questions about the credibility of the prequalification program. There
was an informal warning which led to the inspection of India’s Cipla’s manufacturing plant. It
was found that the bioequivalence studies for an important prequalified ARV drug had major
shortcomings(14). The quality control inspectors had reason to believe that the drugs were
fraudulent. However, they had not found tangible proof that bioequivalence was missing but
there was no proof of its presence either. WHO has in place strict regulation regarding
bioequivalence studies, incorporating carrying out inspections of entities that performed specific
studies on manufacturers behalf. There was confusion that resulted from distinguishing proof of
lack and lack of proof among the stakeholders(15).
This information put WHO in a tough space. Four generic ARV drugs and four
originators were prequalified. There was mounting pressure from rich countries that finance
WHO and were against prequalified generic drugs. WHO faced criticism from activist who
argued out that there was conspiracy among the organization and rich countries meant to have
very high standards in place that would kick out generic drug producers from poor countries
through elimination from prequalification(16).
The technicalities in this case were however clear and Cipla’s drugs had to be delisted
from the qualified list until a time when there was proper establishment of bioequivalence. The
evidence was a major blow to generic products as it proved that despite their cost effectiveness,
they were unreliable. This made WHO halt publication of the information immediately which

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later came back to haunt them as they were viewed by the world and specifically the rich
countries as protectors of ineffective generic drugs. WHO reputation was damaged as their
quality checks were put in question(17).
Pressure mounted on WHO until Cipla was delisted. This was done after WHO sat down
with activists and other stakeholders and informed them of the decision to eliminate further
public pressure. Most organizations such as the Medical Humanitarian Organization argued that
coming out with information on challenges of the prequalification process was a symbol of the
strength of the program. The decision to delist Cipla product was described as a short term pain
for better things in the long term(16). The Indian generic industry was hardest hit but a clear
indication of demand for quality could not be misunderstood. More generic drugs from other
companies such as Ranbaxy Laboratories were delisted for failing to meet quality test.
Stakeholders in the industry had a difficult time understanding why important ARV drugs were
delisted by WHO based on guidelines that did not apply to any jurisdiction(18). A number of
national AIDS programs in third world nations and developing nations were frustrated and hard a
difficult time finding effective alternatives. Consignments of ARV drugs were returned to
pharmaceutical companies by organizations such as UNICEF.
WHO prequalification program faced opposition which eventually reinforced further the
organization’s mission and goals. Two factors influenced its growth and survival at the difficult
time. This were support from donors and its purchasing power. Bill and Melinda Gates
Foundation came to understand the impact of the WHO prequalified program concept and
provided great financial and professional support to the program. UNITAID has also offered
support to the program since its birth in 2006.

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Current activities and successes of WHO’s prequalified program

Since its inception in 2001, WHO prequalified program has seen more than three hundred
and fifty finished pharmaceutical products prequalified. There has only been removal of twenty
products from the prequalified list whereby most where removed at the behest of the
manufacturer. The initial focus of the program was prequalification of medicines meant for the
treatment of TB, HIV and malaria. The programs mandate was extended which saw it cover
reproductive health medication, influenza pandemic medication and acute diarrhea in children
medication.
The time frame for prequalification is not constant and mainly depends on the dossiers
quality in addition to the experience of the producer with regards to stringent evaluation.
Currently, prequalification of a new drug can take three months in a scenario whereby presented
data s complete while showing that the product is in compliance of the set standards (19). When
manufacturers are fast while responding to queries from WHO’s assessment team, the process
can be faster. The fastest prequalification recorded so far for a generic drug was six weeks. In
2010, WHO started prequalifying Active Pharmaceutical Ingredients (API) which plays a critical
role in medicine development. In 2013 alone, WHO prequalification program approved twenty-
three APIs (19).
The program’s success has seen its list of prequalified medicine being used by many
organizations and entities that want to make purchases of medicine in bulk whether at national or
global level as exhibited by Global Fund. The program has prequalified approximately ninety
percent of market of malaria, TB and ARV drugs for UNICEF, UNITAID and, the Global Fund
(20). The program has attained huge milestones in ensuring that limited resources for health go

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an extra mile since they are not spent on expensive drugs or drugs whose effectiveness, safety
and quality is not known.

The future of WHO prequalification Program

WHO prequalification program has a solid future. Currently, there is a global health
pandemic as a result of COVID-19. WHO prequalification program can help fast track the
approval of effective and quality drugs geared towards the management of this disease that has
crippled economies globally. One of the concerns about the program is about the longevity and
relevance of the WHO prequalification program. Undoubtedly, the program will remain relevant
for as long as middle-income countries and low-income countries require assistance from UN
agencies in procuring medicine. The WHO prequalification program also plays an important role
in aiding national regulatory agencies that do not have the ability to evaluate the quality of drugs
produced by their country or imported to their country (21). This is an area that will still be
relevant in the future.
There will be a continued need for cheaper drugs globally that are effective and of high
quality. This program has played a critical role in improving the quality of generic drugs such as
ARVs that have helped many who would have otherwise missed out due to the high price tags
from other drugs (22). There being a long list of approved products is a strong pointer that there
is a market for the medicines.
The program’s mandate of saving lives and cutting back on costs cannot be obsolete.
Entities and stakeholders are continuously looking for effective ways cutting down on cost while
maintaining quality which in this case is effective and quality medicine. In 2009, it was
estimated that the program’s return on investment (ROI) for every dollar spent on
prequalification was $170(9) (23). This ROI is very high. A report by USAID and Supply Chain

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Management Systems revealed savings of up to $ 1.1 billion over a period of six years through
purchasing generic medicine as opposed to branded medicine (24).
Conclusion

Since its inception, WHO prequalification program has played a significant role in
improving public health and access to healthcare in general. The program has been able to
regulate the quality and effectiveness of generic drugs produced to combat diseases such as HIV,
Malaria and TB. The program has seen both good and bad days. It has faced resistance from rich
countries and big pharmaceuticals who would love to protect their monopoly and experience
bigger profits. It has also experienced tremendous support from donors such as the Bill and
Melinda Gates foundation whose continued support has seen the program gain access to more
resources thus achieving its core mandate effectively. Donors and consumers of medicine have a
role to play when it comes to continuously demanding quality assurance and fight the temptation
of going for the cheapest medicine that might not be of quality. Millions of lives have been saved
by this program globally. The program should continuously strive to serve the public good.

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