Recently govt of India has directed pharmaceutical manufacturers to prove the safety and efficacy of fixed dose combinations (FDCs) by August 30.
On the face of it one may be inclined to welcome it as a step in the right direction and at the same time few doctors even started doubting the quality of FDCs. However, the problem should not be viewed superficially as it requires deep scientific studies by experts in pharmaceutical sciences.

It has become a fashion for everybody from the doctors to columnists to social workers to pass judgement on the topics they have little knowledge. For example, with reference to FDCs, an editor, doctor of a medical journal has announced an ‘invention’ that in FDCs when A+B is mixed the resultant product is not AB but ‘C’. It shows he has not come out of his high school chemistry!

Pharmaceutical chemistry which deals with physical and chemical properties of thousands of chemicals used in formulations is not a subject which any one can interpret just like that. It has a minimum of 8 theory and 8 practical papers which requires at least 4 years time to graduate and another 2 years to master it. MBBS course do not have even a single paper of pharmaceutical chemistry in its Syllabus. [But journalists ask only doctor’s opinion on combining drugs! What an irony!]. On the other hand pharmacy graduates are studying all these papers in so many years and there is no other course which covers it from fundamental to specialization. [That is why pharmacy graduates are opposing MSc pharmaceutical chemistry course for BSc graduates, who are just superimposed as postgraduates without studying fundamentals of the subject.

What is the need for FDC?
First of all let us be clear on the need or otherwise of combining drugs. Why drugs are combined? Most of the time, it is for the convenience and benefit of the patient and then the prescriber. Diseases or patient conditions are so much complicated that they need be given many drugs at the same time. Patients are with multiple diseases or under diagnosis. Till their condition is correctly diagnosed they have to be treated symptomatically and which results in prescribing multiple drugs at the same time, known as poly pharmacy. This has many inherent problems like patient’s confusion, non-compliance and cost. If the doctor is not able to prescribe minimum number of doses and drugs most of the patients either ignore or refuse or forget their medicines. Remember any amount of counselling patients will not improve the situation.

There is also necessity to combine drugs as single drugs are becoming ineffective because of misuse, resistance etc. Also many diseases require multiple drug regimens. For example an inflammation is accompanied by pain. So it is essential to go for one anti inflammatory [like Diclofenac] and one analgesic or pain reliever [like Paracetamol or Analgin]. Instead of prescribing these 2 tablets separately, what is wrong if we combine them in one tablet? If the inflammation is due to infection then one more drug [An antibiotic] is needed. Think of patients already taking few drugs for existing diseases like, Diabetics, BP, or TB etc. What will happen if FDCs are not there? Patients has to take 6 or 7 varieties of tablets with time gap, in many divided doses so that the drugs are not mixing and reacting inside their body. Otherwise it is one and the same to take FDC or single ingredient drug. Is it always feasible? Again multiple drugs put the patients into the same risk of drug-drug interaction as alleged for FDCs.

How drugs are combined?
Basically, only the chemicals which do not react with each other are mixed in FDCs. Even if reacting chemicals has to be mixed together, that is studied before hand and suitable modifications are carried out to make it non reactive or safer. It is proved by the fact that each active ingredient of the formulation is individually analysed in Govt and private reputed labs and found to be in correct quantity as claimed in the label, even after the mixing was made months and years back in formulation units. How it is possible if it has resulted in a new product as claimed by the learned doctor? Any one with little knowledge of analytical chemistry can understand this.

If there is a doubt, two ingredients of a formulation may react in due course of time, they are separated even inside the formulation by various techniques using the knowledge of ‘pharmaceutics’ - another big subject that deals with formulation techniques. Manufacturing and quality control pharmacists burn mid night oil to develop new formulations and analytical methods for them. Only after thorough study of each and every ingredient of the formulation, theoretically, practically as well as by making many trial batches, they are manufactured and marketed. Control samples of all these batches are periodically tested for stability, potency, toxicity etc. Hence, we need not have any apprehension about all the FDCs and jump to the conclusion they are all harmful.

Deep study
Of course drugs may become harmful after consumed by patients because of complex human biochemistry. That aspect is taken care of during various phases of clinical trials of new drugs. What happened to the patient after consuming a drug is monitored by clinical pharmacists, clinical pharmacologists and biochemists during and after this drug discovery process. Since individual drugs had undergone these rigorous tests already, they are combined in FDCs. What is remaining to test is whether they react after mixing. That is studied as detailed above. Only after submitting ‘Therapeutic Justification’ for FDC, apart from its stability, potency and other data, manufacturers are getting licence to manufacture it from Drugs Control People.

Still if there is doubt and we have to prove FDCs are safer, we need to undertake clinical trials, similar to the one carried out for new molecules or drugs, which will definitely push up the cost by many fold. As the individual drugs of FDC is not new, already tested by clinical trial and available in pharmacies, the cost of clinical trials of FDCs cannot be recovered by raising its price. If the FDC is very costlier, the very purpose of its marketing is defeated, as people can purchase cheaper individual drugs. It is not to argue, clinical trials are not at all required for FDCs. Govt labs can carry out clinical trials for doubtful FDCs in the interest of its own citizens. In the meanwhile doctors can prescribe those drugs restrictively with caution on their own, as nobody is compelling them to prescribe a particular drug.

Moreover, if something goes wrong with considerable number of patients after taking a doubtful FDC, it has to be verified by studying various pharmacokinetic and pharmacodynamic parameters of the patient and the results should be published in reputed medical and pharmacy journals before arriving at a decision to withdraw a drug from market.

The greatest problem with such decision is, the result of such study in one country on one race of people need not be same for another country with different race of people, as pharmacokinetic [what the body does to the drug] and pharmacodynamic [what the drug does to the body] of the drug may differ widely from patient to patient. But without understanding all these problems people, especially parliamentarians and other politicians loose patience and make lot of cue and cry about stopping or not stopping of a particular drug in India.

Combinations and competitions
In our anxiety to stop irrational formulations, we should not forgo the benefits of rational formulations. There are scores of such formulations and their combinations in the text books of medicine and pharmacy. There is a big chapter dealing with ‘beneficial drug-drug interactions’ in those books which describes these benefits as potentiation, synergism etc. Most of the time, the dose of a drug is reduced when given in combination with another drug of same pharmacological activity. Thus all aspects of combining drugs are taken care of during formulation stage itself. So be hopeful and don’t get carried away by wild allegations and casual statements on the safety of these drugs. No one is going to object if irrational and harmful FDCs are weeded out, but don’t  create fear in the mind of general public by sweeping general statements.

One must remember there is cut throat competition for catching market for a drug. Competitors may go to any extend to spoil the market of rival, successful formulator. One example is recent ban on the best pain reliever ‘Analgin’ by Govt. There is strong suspicion that it is banned because of continuous pressure from vested interests, as Analgin was invented by former Soviet Union [USSR]. Another example is the recent controversy about ‘Pioglitazone’ - an anti diabetes drug. Thus politics and vested interests play a larger role in all these episodes. Don’t loose sight of it. We periodically come across the news of “planted (pseudo) research articles” in scientific journals either to mudsling the competitor’s product or to promote their own product. Hence, be vigilant, at the same time don’t loose patience and fall into the hands of mischievous elements.

Also the present direction to submit safety data is issued by the DCGI, because the licences to manufacture these FDCs were issued earlier by state drugs controllers. Thus there are some administrative problems clouding this episode, not the quality of FDCs alone!.