[e-drug] Relying on Stringent Drug Regulatory Authorities? (5)

E-DRUG: Relying on Stringent Drug Regulatory Authorities? (5)
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Thanks Patrick, Bonface and Raffaella!

We have been unclear in the original message where we used wording like
'instead of maintaining a Suriname DRA...'

1) sorry, we didn't mean to abolish the Surinamese DRA; we agree with
the comments made that the in-country activities like product
registration (at the minimum as a basic dossier validation), quality
control and pharmaco-vigilance, licensing of pharmacies, importers, and
wholesalers still needs to be operationalized in-country by the
competent authority and be backed up by adequate legislation and
political support. Especially in view of post-marketing assurances.
Obviously strengthened as much as possible where it is found to be weak
e.g. dossier evaluation, inspectorate, analytical laboratory functions.
Small DRA's in countries with little voice to complain may benefit from
the work done for same products in stronger developed countries.

Nevertheless in our original posting, we would like to hear about other
views where E-druggers think that assuming that 'pre-market quality'
from the Netherlands, Greece, Malaysia or South-Africa (just to name a
few) on the basis of '...actually being on the market in country of
origin', is too naive. Or maybe too easy. We also like to specify
'actually on the market' more in detail. For instance a UKMHRA approval
could be provided by a supplier for a product manufactured in India with
barely a significant number of batches being actually used in the UK, or
couldn't it?. Then there are dossiers for a EU country and formulas used
for other markets. Or the approval sometimes relates to one of multiple
production blocks or a production line only and there may be conditional
compliance's to be fulfilled...

2) Maybe we could make the list of stringent regulated countries more
concrete by summarizing as follows:

Argentina, Australia, Austria, Belgium, Canada, Cyprus, Czech Republic,
Denmark, Estonia, Finland, France, Germany, Greece, Hungary, Ireland,
Italy, Japan, Latvia, Liechtenstein, Lithuania, Luxembourg, Malaysia,
Malta, Netherlands, Norway, Poland, Portugal, Romania, Singapore,
Slovakia, Slovenia, Spain, Sweden, Switzerland, South Africa, United
Kingdom, United States of America.
In italic: seen as adopting ICH principles (CTD dossier) but not (yet)
member of PIC/s (GMP recognition); underlined: PIC/s member but not
necessarily (yet) adopting CTD dossier format.

Feedback welcome. We would think that some others could be at PIC/s
level but cannot substantiate that.

Where in between would you place Brazil, Cuba, Mexico, Puerto Rico,
Morocco, China, India, Pakistan, Iran, Russia, Jordan, Oman, Sri Lanka,
Bangladesh and Indonesia as (contract manufacturing) exporters of
generic medicines or even vaccines?

3) A formal exchange of data between regulators in the above countries
and a small DRA is indeed a very good point to make because essential
drugs do circle around a relative limited list of sources in not too
many countries (per region or otherwise). The overlap of the actual
products/sources between the stringent countries and a small DRA in a
developing country may nevertheless be too small to collaborate on
product or factory level. In fact the current WHO CoPP certification
scheme is what we have in practice and 'it has lost some of its
credibility'. We like to see more (regional) collaborations and joint
inspections in between DRAs or under e.g. stewardship of the WHO (ICDRA)
which then can also be an impulse for regional procurement systems. In
case stringent DRAs are prepared to share information and/or capacity
this would increase the shorter-term efficiency of the Suriname DRA
while working on capacity building (long term, possibly thru formal
partnership with some stronger sister-DRAs). What are the barriers
really besides statutory jurisdiction and probably confidentiality
issues?

4) We believe that PIC/s inspectors, besides harmonizing inspection
standards with the GMPs, look at product quality too; the pharmacopoeias
(formulations and drug substances) are as much as GMP an inspection tool
to assure product quality. We are not trying to have a small DRA
re-establishing efficacy and safety of well established generics. We do
think that PIC/s could - in principle - be a perfect school for smaller
DRA's especially those from developing countries.

5) We underline the proven value and importance of the WHO PQ program
like Bonface replied. Yet, more is needed and there are certain
loopholes with the list as well; it is based on a voluntary
participation, and in fact it delivers a recommendation, however strong
[for UN agencies] but with certain disclaimers (e.g. 'Inclusion in this
list does not constitute an endorsement, or warranty of the fitness, by
WHO of any product for a particular purpose, including in regard to its
safety and/or efficacy'). Such disclaimer probably allowed inspectorates
from the stringent countries to share their resources. Which of course
is all good and offers opportunities for training of smaller DRAs as
well but it can obviously not be a basis to free-ride. In addition (like
Patrick also hinted to) the list e.g. still does not specify the API
source for pre-qualified products. Then besides WHO and Unicef there
seem to be more possible intermediates because for time being there is
still a range of essential drugs outside the range of
pre-qualification... so we would like to read more about the
pre-qualification of procurement agents using sources outside the ones
listed as stringent above but providing assurances to meet the stringent
norms and standards).

Looking forward to more discussion to bring relevant 'stringent DRA,
reliance pro's and cons' on the table

Regards

Pascal Verhoeven
Pharmacist/independent consultant
Netherlands
verhoeven.pascal@gmail.com

Rob Verhage, pharmacist
HERA Pharmaceutical Consultant
Tawajakoerastraat 4
PO Box 4002
Paramaribo
Suriname
+597 438966 or +597 8561109
verhager@cq-link.sr

E-DRUG: Relying on Stringent Drug Regulatory Authorities? (6)
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I think Pascal and Rob have asked an important and sophisticated series of
questions about reliance on stringent drug regulatory authorities
(SDRAs)primarily with respect to reliance on determinations of safety and
efficacy and secondarily with respect to reliance/cooperation/training with
respect to GMP quality. They have clarified that even poorer developing
countries need to maintain many other DRA capacities including
pharmacovigilance, etc.

The benefits of a reliance system are multiple:

1. It reduces demands on DRAs that have limited capacity that is best used
on other functions;
2. It expedites the registration of essential (and newer priority)
medicines;
3. It could allow registration of generic equivalents even when the
innovator product is not yet registered -- the DRA could rely on the fact
of prior registration elsewhere to satisfy the safety and efficacy of the
reference product where bioequivalent or other therapeutic equivalency data
is submitted re a follow-on product (note: this benefit is especially
important to smaller and poorer countries where R&D companies often delay
registration; note as well that this option takes one weapon out of the
hands of Big Pharma which has been known to withdraw or refuse product
registration applications in retaliation for countries using TRIPS
compliant mechanisms to access cheaper generic equivalents, e.g., Abbott in
Thailand re LPN/r; finally note that this option could expedite
registration of therapeutically appropriate fixed-dose combination generic
medicines);
4. This option could and should allow vicarious reliance on WHO
prequalification since those procedures closely parallel those used by
SDRAs.

Despite these advantages, there are certain risks to such reliance
including:

1. The cost/benefit ratio may differ between SDRA countries and countries
relying on prior registration based on disease burdens and population
characteristics, and other factors. This variance could go in both
directions, but more commonly countries might be tempted to deny
registration for products that have been turned down by a SDRA even though
the disease prevalence and/or the lack of alternative therapies might
suggest a different outcome in a poor country. In particular, cost/benefit
ratios for certain vaccines could differ substantially. Likewise, it would
not necessarily make sense to register every product accepted by a SDRA
where population characteristics, such as nutrition, might exaccerbate
adverse side effects.
2. Care must be taken to keep track of changes in registration, both
actions by SDRAs (product withdrawals, Black Box warnings etc) and even
voluntary product withdrawals (much harder to monitor).
3. There is certainly evidence that SDRAs sometimes make mistakes and/or
that applicants have provided misleading information. More commonly,
increased information becomes available as the product is made available
over longer periods of time and to larger and more diverse populations.
Frankly, however, conducting dossier evaluations domestically would
probably not ameliorate this problem.
4. There must be vigilance that the registered products are being produced
at the same manufacturing facilities where GMP have been confirmed.
Alternatively, the new facilities must be inspected and reviewed.

On balance, I think the arguments for reliance on SDRAs for baseline
determinations of safety and efficacy (and GMP) are stronger than the
counterarguments. Getting proven life-saving drugs to the market quicker
and having more expedited procedures to access generics even when the
innovator is dragging its feet or flexing its muscles is incredibly
important. Conserving scarce regulatory resources for local quality
control across the chain of distribution is also vitally important.

One final note, countries that improvidently adopt data exclusivity rules,
including rules that would prohibit reliance on the fact of foreign
registration by a SDRA, are shooting themselves in the foot with respect to
adopting this option. The U.S. and E.E. continue to seek stronger forms of
data excluivity in many of their recent trade agreements and developing
countries frequently seem to misunderstand the impact of such agreements on
some of their policy options.

Brook

Professor Brook K. Baker, Health GAP
Northeastern U. School of Law
Program on Human Rights and the Global Economy
400 Huntington Ave.
Boston, MA 02115
617-373-3217 (office)
617-259-0760 (cell)

E-DRUG: Relying on Stringent Drug Regulatory Authorities? (7)
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Dear Colleagues,

I would like to mention that there are instances when "reliance" on a "Stringent DRA" does not always meet the immediate needs of a DRA in a developing country.

I recall the case involving importation and registration of Zinc Sulfate (Dispersible) Tablets (USP) into one developing country which, by my reckoning, has one of the more progressive DRAs. Many e-drug colleagues may be familiar with this lingering problem with the registration of Zinc Sulfate tablets in some countries. The DRA in the importing developing country insisted, understandably, that for registration and eventual importation of the product, they required a Certificate of Pharmaceutical Product from the SDRA. However, the manufacturer in the exporting country with the SDRA had not formally filed for registration in the exporting country, because the use of Zinc Sulfate for diarrhea control is apparently not clinically and therefore commercially an attractive issue in the country. With some pressure, I suppose, the SDRA eventually issued a COPP to the DRA in the developing country but, whilst completing section 2.B.3. of the certificate i.e. "Why is marketing authorization lacking? (not required/not requested/under consideration/refused)", a statement was made by the SDRA to the effect that this was because they did not have the safety and efficacy evidence. Of course, they could not have the evidence because the manufacturer had not formally submitted a dossier. Indeed, the literature is now awash with solid evidence of the safety and efficacy of Zinc in diarrhea control. This therefore became a Catch 22 situation.

The point I make is that the DRA in the developing country wanted to "rely" on the Stringent DRA, but the latter could not provide the legal basis of "reliance", because technical evidence was not formally before it.
Such an incident gives further support to those colleagues who believe that no matter how much one may wish to rely on external agents; this should only be as a milestone on the longer strategic route to self reliance.

Murtada M. Sesay
Senior Pharmaceutical Product/Supply Chain Officer
UNOPS India Procurement Office
11, Golf Links
New Delhi - 110.003
India
Tel.: +91 11 3041 7430 (Direct), +91 11 3041 7430 (switchboard)
Fax: +91 11 4350 8527
Email: Murtadas@unops.org