Friday, August 07, 2009

GENERICS Vs BRANDED DRUGS : With a paragraph on generic Drug-Eluting Stents.

This piece is written for the mass media, following the workshop on " The Malaysian National Medicines Policy-mid term review 2009 ". It is reproduced here for infromation to all of you.

With rising cost in healthcare, many countries find that one of the easiest way to reduce healthcare cost is to switch to the use of generic drugs. Of course, the healthcare providers make the assumption that generic drugs is the same as the branded drugs, albeit without the bigger price tag. Is this true? Are generic drugs the same, especially in terms of efficacy ( after all drugs are used in the treatment of disease conditions ).

Let me begin with a few definitions. ( Medical science always like to define things so that you are sure what we are talking about ).

Medical drugs are chemical compounds prescribed by qualified medical practitioners, in the treatment of disease conditions. They are usually prescribed for a given duration, or in chronic disease states, may be given long term. Their use are subjected to approval by the relevant national authorities.

Branded drugs are drugs produced by a company ( usually multi-national companies-MNC ) with a patent on them. These drugs are usually well researched for safety and efficacy, and are proven by large scale clinical trials to be of benefit in curing or controlling disease states.
On the other hand, generic drugs are drugs produced by any company, once the patency has expired, as a copycat of the branded drug.
The use of both branded drugs and generic drugs are subjected to approval by the relevant national authorities.
Generic drugs are of course cheaper, as the generic drug companies save clinical research, marketing and promotion. And of course, competition also drives down cost.

Because of severe competition in both the branded drugs and the generic drug markets, most MNC have their own generic division so that they can also produce their own generics to compete in the generic drug market.

What then is the difference between generic drugs and branded drugs?

I always tell my patients, whenever they ask, that the difference between generic drugs and branded drugs is in the quality control. Here, one must not think that, in the manufacture of a drug, one only has to consider the active ingredient, important as that may be. The drug that you take does not consist of only the active ingredient. As an illustration, a drug consist of the active compound ( that which helps to make the patient well ), another compound added to make the active compound stable, another compound added to make the compound soluble so that it can be absorbed in whatever form it is to be taken. Some even add some colouring to the drug, so that it does not have the same colour as the original branded drug. Of course with so many chemical compounds added, the quality of the chemicals sourced becomes important, especially the expiry dates. To cut down the cost of production ( generic drugs must be cheap and yet have good profit margin ) what is there to stop the profit oriented companies to use good quality chemicals in the batches scheduled to be tested for approvals and once approval is granted, all subsequent batches have chemicals with short expiry dates ( cheap stocks ). After all, non of us would knowingly take expired food stuff. Therefore, if quality control is lax ( both by the manufacturers and also the enforcement authorities ), the generic drugs would have highly variable efficacy and safety. In fact, some generic drugs are no better then sugar pills or flour pills.
Of course there are standards to test these things. Each drug, to be registered, is required to undergo “ bio-availability “ studies, and “ bio-equivalence “ studies. What do these mean?
Bio-availability means how much of the drug, once absorbed, into the blood stream, is available in the blood serum, for it to act at the target sites in the body. This can be tested in the laboratory.
Bio-equivalence means that the generic drug is tested in the laboratory ( animal testing ) or given to normal humans, to observe their pharmacological action, to see if they have an equivalent action, as the branded drug. For both of these, the standards are that the generic drug have to be +/-20% of the branded.
Overall, we can sum up all that I have written so far, in that generic drug manufacturers, like branded drug manufacturers, must observe and adhere to “ Good Manufacturing Practice “ standards. This good manufacturing practice includes details of manufacture and sourcing of the chemicals and their expiry dates, details on the control of all stages in the manufacture of the drug, instructions and procedures are written clearly in unambiguous language, details are meticulously recorded and kept for inspection, operators are well trained to carry out and document procedures, deviations from the procedure are investigated and recorded, records of manufacture and distribution are kept so that anyone batch can be trace, in the event of a recall, a system of recall is detailed in the event that this is necessary.
Good Manufacturing Practice ( GMP ), is not a prescription on how to manufacture drugs. It is a set of principles for the company to adhere to to guide them to manufacture drugs of a sufficient standard. In fact, each country have their own GMPs. The WHO have their own GMP, the European Union have theirs, The US have their FDA version. The UK have the “ orange book “ or the Medicines Act ( 1968 ). Good manufacturing practice must also come with good enforcement. Besides checking that companies producing generic drugs adhere to GMP, enforcement agencies must also undertake post-marketing surveillance, to see how the drug is performing in the market place. There should also be a system of adverse events reporting, so that if that batch is bad, it can be recall, as it happens every now and then with some branded drugs. I think that it is fair to say that post-marketing surveillance and adverse events reporting in Malaysia, still have much room for improvement.
Because each country and each company, have their own standards of GMP and also enforcement, it is reasonable to assume that not all generic drugs are the same. The generic drugs that are produced in countries with GMP and good enforcement agencies, thend to be of a higher quality, and the generic drugs manufactured in countries with poor GMP standards and also with poor enforcement agencies, tend to be of poor quality.

We therefore differentiate even between generics. Many MNC drug companies with branded drugs, have began to set up generic divisions to manufacture generic drugs. Because of their branding and corporate culture ( transparency, accountability, social responsibility and the light ), we are confident that their generic drugs will be of almost equal quality, when compared to their own branded drugs. There are some first world countries who manufacture generic drugs of good quality, like generic drugs from Canada, Israel ( not used here ), Sweden, France, Germany, Australia, USA etc. Then there are generic drugs manufactured in Brazil, India, Taiwan, Indonesia etc, and there are generic drugs manufactured locally. Not all generic drugs are the same. That may also be why not all generic drugs have the same price. Do you wish to take a chance with generic drugs, having read all that have been written, for your health and maybe your life.

Although this article is written primarily to discuss generic drugs, it is equally applicable to generic devices like drug-eluting stents. Drug-eluting stents are slotted metal-tubes that we insert, via a process called angioplasty, into coronary arteries, to treat blockages in coronary arteries. As it is commonly known, angioplasty’s Achilles heel is restenosis ( the process of re-blockage of the stent after successful implantation. Re-stenosis is due to a process of excessive scar healing following the stent placement. To address this issue, the innovative cardiologist have invented the drug-eluting stent. This drug-eluting stent or DES for short, has a metal platform ( like the old stents ), on which is coated a polymer coating, in which drugs to combat scar tissue formation is impregnated. DES have proven very successful in the fight against CAD and in-particular against re-stenosis following coronary stenting. Of course DES do not come cheap. Because of the cost of DES, we now see the emergence of generic DES. Of course generic DES manufacture must also adhere to the “ Good Manufacture Practice “. ( To the best of my knowledge, there are no generic DES manufactured in Malaysia ). Therefore like generic drugs, there are also different generic DES of different quality, safety and efficacy. This generic DES issue is somewhat more serious, ( and I am not saying that the generic drug issue is not a serious issue ), because these generic DES are permanent implants in the coronary arteries, so they can create long-term harm. It is important to note that unlike drugs ( at the present all drugs must be registered with the Ministry of Health Malaysia ), presently registration of medical devices and their use is not yet compulsory in Malaysia. It is very much voluntary.

If I have not been clear from the beginning, the purpose of this article is to inform the public about the issue of generic drugs versus branded drugs. It is my sincere hope that when your doctor prescribe the drugs for the treatment of your condition, you should be better empowered to ask the relevant questions about generic drugs and their safety and efficacy, and then make an informed choice. You are the patient, and you have a say in whatever treatment given to you.

Remember, the saying is true, “ cheap things no good, good things no cheap “ . Basically, you get what you pay for.


Mazuwin said...

As stipulated under the Control of Drugs and Cosmetic Regulations 1984, all medicines must be registered with the Drug Control Authority (DCA), Ministry of Health, Malaysia before they can be manufactured, imported, distributed or administered. In Malaysia, all medicines regardless of whether they are innovator products or generics undergo a scientific evaluation process to establish the safety, quality and efficacy of the product which is to be marketed in Malaysia.

Generic medicines must have specifications which are similar to the branded medicines to ensure that they can be used for the same purpose and in the same way. Manufacturers of generic medicines have to comply with the same standards as manufacturers of branded medicines but their price may be lower as the manufacturers do not incur the costs associated with the research and development of innovative medicines. The reduction in cost is NOT because quality has been compromised during the manufacturing of the product.

The regulatory requirements in Malaysia are similar to that of other developed countries. The Control of Drugs and Cosmetics Regulations 1984 requires that the standard of manufacture and quality control of medicines, branded or generics, manufactured locally and outside Malaysia be taken into consideration before the medicines are registered.

As Malaysia is a member of the Pharmaceuticals Inspection Cooperation Scheme ( PIC/S), the code and standards of Good Manufacturing Practice (GMP) is the same as that used in Australia, Canada and Europe. Manufacturers located within Malaysia are subjected to licensing and periodic GMP audits. Foreign manufacturers of imported medicines are also subjected to GMP conformity assessment whereby the manufacturers are required to provide acceptable evidence that the premise conforms to current GMP requirements.

Where acceptable GMP evidence is not available or where the document submitted is insufficient or not satisfactory to demonstrate equivalent GMP standards, the DCA may require an on-site audit of the foreign manufacturer to be carried out

Mazuwin said...

Apart from GMP, the regulatory guidelines and standards for the registration of products are constantly reviewed to ensure that requirements are in line with international standards and current practices. As part of the ASEAN harmonisation initiatives, ASEAN Common Technical Requirements and Guidelines have been developed based on the International Conference on Harmonisation (ICH) and the World Health Organisation (WHO) technical requirements and guidelines. Compliance with these requirements have already been enforced in several ASEAN countries.

As generic medicines contain well documented active ingredients, it is the global practice to accept bioequivalence (BE) studies in liew of clinical trials as proof of quality and efficacy. The Ministry of Health, Malaysia implemented a requirement on the conduct of bioequivalence studies on generic medicines since 1999 and to date, there are 95 active ingredients for which BE studies are required as a pre-requisite for registration.

BE studies are conducted using humans as subjects, the plasma concentration vs time curve is used to assess the rate (Cmax) and extent of absorption (AUC). To show bioequivalence, it requires 90% confidence interval limits in the range of 80-125% based upon logarithm transformed AUC and Cmax data and this has been adopted by most of the drug regulatory bodies in the world.

Two medicinal products containing the same active substances are considered bioequivalent if their bioavailabilities (rate and extent) after administration in the same molar dose lie within these acceptable predefined limits. These limits are set to ensure comparable in vivo performance, ie. similarity in terms of safety and efficacy. Bioequivalence studies does not prove that two medicines of the same drug are exactly identical, but it shows two medicines are similar enough to be regarded as equivalent within specified limit that are clinically tolerable.

The DCA will ensure that marketed medicines comply with the strict registration requirements and therefore, all registered medicines either branded or generics are subjected to post–market surveillance and adverse drug reactions monitoring program. Healthcare professionals and consumers are responsible to report any adverse drug reactions and product complaints to the authority. The DCA does not hesitate to remove unsafe or sub-standard products from the market.

The public can rest assured that all medicines, branded or generics, registered by the DCA are safe, efficacious and of good quality. Generics medicines do offer patients with accessible and affordable medicines. Although generics bypass the expense and time required to demonstrate the drugs efficacy and safety through clinical trials but generics still need to conform to same standard of quality, efficacy and safety required of the branded medicines. Therefore, it is important for Malaysians to be aware that ‘Cheap Price is not an indicator or a perception of ‘Low Quality’ medicines.