Serious Concerns on the Indian Drug Industry
DEPARTMENT-RELATED PARLIAMENTARY STANDING COMMITTEE ON HEALTH AND FAMILY WELFARE
FIFTY-NINTH REPORT ON THE FUNCTIONING OF THE CENTRAL DRUGS STANDARD CONTROL ORGANISATION (CDSCO)
(PRESENTED TO THE RAJYA SABHA ON 8TH MAY, 2012) & (LAID ON THE TABLE OF THE LOK SABHA ON 8TH MAY, 2012
1.1 Drugs are an integral and inseparable part of medical care. As per the directory of pharmaceutical manufacturing units in India brought out by the National Pharmaceutical Pricing Authority in 2007, more than 10,500 drug manufacturers are operating in the country with estimated turnover of just over Rs. 50,000 crore for domestic sale alone.
1.2 Medicines apart from their critical role in alleviating human suffering and saving lives have very sensitive and typical dimensions for a variety of reasons. They are the only commodity for which the consumers have neither a role to play nor are they able to make any informed chokes except to buy and consume whatever is prescribed or dispensed to them because of the following reasons:
• Drug regulators decide which medicines can be marketed;
• Pharmaceutical companies either produce or import drugs that they can profitably sell;
• Doctors decide which drugs and brands to prescribe;
• Consumers are totally dependent on and at the mercy of external entities to protect their interests.
1.3 It is because of these typical dimensions that the state’s responsibility to regulate the import, manufacture and sale of medicines so as to ensure that they are both safe, effective and of standard quality acquire almost sacrosanct dimensions. Under the circumstances, effective, transparent drug regulation free from commercial influences is essential to ensure the safety, efficacy and quality of drugs with just one objective, i.e., welfare of patients.
1.4 Taking into account the immense importance and impact of drug regulation on humanity, the Committee examined the functioning of The Central Drugs Standards Control Organisation (CDSCO), the agency mandated with the task of drug regulation in India to determine if rules and laws were being implemented efficiently and honestly in the interest of patients. It did not go into the scientific Issues such as merits of medicines being sold in the country. As the successive narrative would unravel, the drug regulatory system in the counhy suffers from several deficiencies and shortcomings, some systemic and severa] manmade.
1.5 Drug regulation covers many functions, namely:
• Marketing approval of new medicines based on safety and efficacy studies,
• Licensing and monitoring of manufacturing facilities and distribution channels,
• Post-marketing adverse drug reaction (ADR) monitoring,
• Quality control (QC),
• Periodic review and re-evaluation of approved drugs,
• Control of drug promotion
• Regulation of drug trials.
1.6 While most functions pertaining to drug regulation come under the jurisdiction of Central Government and are carried out by the Central Drug Standards Conhol Organization (CDSCO), others viz. licensing and monitoring of manufacturing units and distribution channels; quality control etc. are carried on by state level drugs authorities under the administrative control of State Governments.
1.7 Drugs and Cosmetics Act, 1940 and Rules 1945, Drugs & Magic Remedies (Objectionable Advertisements) Act, 1954 as amended from time to time are the principal legislations that govern the functioning of CDSCO and state drug authorities.
1.8 Drugs belonging to various systems of medicine (Allopathy, Homoeopathy, Ayurveda, Siddha and Unani) as well as cosmetics are regulated by CDSCO. However the present Report is confined to the aspect of regulation by the CDSCO and related agencies of drugs used in modem medicine only.
OBSERVATIONS/RECOMMENDATIONS — AT A GLANCE
MANDATE AND STRUCTURE OF CDSCO
The Committee is of the firm opinion that most of the ills besetting the system of drugs regulation in India are mainly due to the skewed priorities and perceptions of CDSCO. For decades together it has been according primacy to the propagation and facilitation of the drugs industry, due to which, unfortunately, the interest of the biggest stakeholder i.e. the consumer has never been ensured. Taking strong exception to this continued neglect of the poor and hapless patient, the Committee recommends that the Mission Statement of CDSCO be formulated forthwith to convey in very unambiguous terms that the organization is solely meant for public health. (Para 2.2)
The Committee notes with serious concern that CDSCO is substantially under-staffed. Of the 327 sanctioned posts, only 124 are occupied. At this rate, what would be the fate of 1,045 additional posts that have been proposed is a moot point. If the manpower requirement of the CDSCO does not correspond with their volume of work, naturally, such shortage of staff strains the ability of the CDSCO to discharge its assigned functions efficiently. This shortcoming needs to be addressed quickly. Consideration can also be given to employ medically qualified persons as Consultants/Advisers (on the pattern of Planning Commission) at suitable rank. (Para 2.19)
The Committee also gathers that the average time taken for the completion of recruitment process is approximately 12 to 15 months. The Committee, therefore, recommends that to overcome the staff shortage, the Ministry should engage professionally qualified persons on short-term contract or on deputation basis until the vacancies are filled up. Due to the very sensitive nature of regulatory work, great care will need to be taken to ensure that persons employed for short periods did not and will not have Conflict of Interest for a specified period. (Para 2.20)
At the same time, the optimal utilization of the current staff in the best interest of public is the responsibility of those who run the CDSCO. In a resource- constrained country like India, it is extremely difficult to meet the demands, however, genuine, of all the State entities in full. Hence, prioritization is the key. For example, work relating to an application for Marketing Approval of a New Drug that will be used by millions and thus have an impact on the well being of public at large in India for years to come, is far more important and urgent than giving permission to a foreign company to conduct clinical trials on an untested new patented, monopoly drug. (Para 2.21)
The Committee also observes that the strengthening of drugs regulatory mechanisms cannot be achieved by manpower augmentation alone. A host of issues involving capacity-building of CDSCO like upgradation of existing offices, setting up of new offices, creation of new central drugs testing laboratories and equipping them with the state-of-the-art technology to enable them to carry out sophisticated analysis of drugs, upgradation of the existing 6 Central Drugs Testing Laboratories, skill development of the regulatory officials, implementation of an effective result-oriented pharmacovigilance programme drawing on global experience, increased transparency in decision-making of CDS CO etc. will have to be addressed before the desired objectives are realized. (Para 2.22)
In the absence of any reasons for unwillingness on the part of medically qualified persons to join CDSCO, the Committee is of the opinion that emoluments and perquisites may not be the main or only reason. It is noticed that minimum prescribed academic qualifications for the post of DCGI is barely B.Pharm. On the other hand for Deputy Drugs Controller (DDC), the prescribed minimum qualification is post-graduation for medically qualified persons. The stumbling block is the requirement that DCGI should have experience in the “manufacture or testing of drugs or enforcement of the provisions of the Drugs and Cosmetic Act for a minimum period of five years.” This requirement virtually excludes even highly qualified medical doctors from occupying the post of DCGI. Moreover the rule stipulates that doctors with post-graduation should be either in pharmacology or microbiology only, thus excluding post-graduates, even doctorates (like DM) in a clinical subject. Besides, highly qualified medical doctors may be reluctant to work under and report to a higher officer with lesser qualifications in a technology driven regulatory authority set-up. Unless these concerns are addressed, it would be difficult to get the desperately required medically qualified professionals on the rolls of CDSCO. (Para 2.23)
QUALIFICATION AND POWERS of DCGI
The Committee fails to understand as to how a graduate in pharmacy or pharmaceutical chemistry (B.Pharm) is being equated with a medical graduate with MD in Pharmacology or Microbiology. Apart from the obvious anomaly, with rapid progress in pharmaceutical and biopharmaceutical fields, there is urgent need to revise the qualifications and experience as minimum eligibility criteria for appointment as DCGI. The Committee is of the view that it is not very rational to give powers to a graduate in pharmacy, who does not have any clinical or research experience to decide the kinds of drugs that can be prescribed by super specialists in clinical medicine such as those holding DM and PhD qualifications and vast experience in the practice of medicine and even research. (Para 3.6)
On a larger plane, the Committee is disillusioned with the qualifications provided in the age old Rules for the head of a crucial authority like CDSCO. The extant Indian system is nowhere in so far as sheer competence and professional qualifications are concerned when compared with countries like USA and UK. There is, therefore, an urgent need to review the qualifications, procedure of selection and appointment, tenure, emoluments, allowances and powers, both administrative and financial of the DCGI. While doing so, the Government may not only rely on the Mashelkar Committee Report which recommended augmented financial powers to DCGI but also take cue from similar mechanisms functioning in some of the developed countries like USA, UK, Canada, etc in order to ensure that only the best professional occupies this onerous responsibility. The Committee should be kept informed of the steps taken to address this issue. (Para 3.7)
In the considered opinion of the Committee, there can never be a more opportune time than now, to usher in these changes recommended by it. The post of DCGI is vacant as of now, with an official holding temporary charge. They, therefore, desire that the government should take immediate measures in terms of their instant recommendations to ensure that CDSCO is headed by an eminent and professionally qualified person. (Para 3.8)
ROLE OF THE STATE DRUG REGULATORY AUTHORITIES
From an analysis of the above facts, the Committee concludes that shortcomings witnessed in respect of coordination with and between the States as also in implementation of applicable legislations in the States are primarily an offshoot of inadequacies in manpower and infrastructure in the States. Strengthening the regulatory mechanism in the States will remain a far cry unless these infirmities are taken care of. (Para 4.5)
Given the lack of adequate resources in the States it would be unrealistic to expect them to improve the infrastructure and increase manpower without Central Assistance for strengthening drug control system. The Committee, therefore, recommends that the Ministry of Health and Family Welfare should work out a fully centrally sponsored scheme for the purpose so that the State Drug Regulatory Authorities do not continue to suffer from lack of infrastructure and manpower anymore. The Committee desires to be kept apprised of the initiatives taken by the Ministry in this regard. (Para 4.6)
It is a matter of grave concern that there are serious shortcomings in Centre-State coordination in the implementation of Drugs & Cosmetics Act and Rules. This, the Committee notes, is despite the Ministry’s own admission that Section 33P of the Drugs and Cosmetics Act contains a provision that enables the Central Government to give such directions to any State Government as may appear to it to be necessary for implementation of any of the provisions of the Drugs and Cosmetics Act and Rules made thereunder. The Committee understands that these provisions are meant to be used sparingly. However, there have been several situations which warrant intervention through Rule 33 P. Therefore the committee hopes that in future the Ministry would not be found wanting in considering the option of using Section 33P to ensure that provisions of central drug acts are implemented uniformly in all states. (Para 4.7)
As regards lack of databank and accurate information, the Committee would like to observe that given the information technology resources currently available, developing an effective system of coordination amongst State Drug Authorities for providing quality and accurate data could have been accomplished long back had the Ministry taken any initiative towards encouraging the States to establish a system of harmonized and inter-connected databanks. Evidently, no serious efforts seem to have been made in this regard. The Committee, however, expects that the Ministry would, at least now, playa more pro-active role in encouraging the States to employ modern information technology in the implementation of tasks assigned to them. At the same time a centralized databank (e.g. licenses issued, cancelled, list of sub-standard drugs, prosecutions etc.) may be created to which all the State Drug Authorities should be linked. (Para 4.8)
CAPACITY-BUILDING OF CENTRAL AND STATE DRUG TESTING LABORATORIES
The Committee agrees that the capacity-building of the Central Drugs Testing Laboratories is the need of the hour. In this era of newer innovations coming up at rapid pace, equipping the Drug Testing Laboratories with the high-end sophisticated equipments is very essential. However, the Committee is aware that monitoring the quality of drugs is primarily the responsibility of the State Drugs Authorities, supplemented by CDSCO, which play a major role in collection of samples and testing them. Without manpower augmentation and up gradation of State Drugs Testing Laboratories, the objective of ensuring availability of quality drugs to the public cannot be realized. The Committee, therefore, recommends strengthening of both Central and State Drug Testing Laboratories. (Para 5.11)
PROVISION OF REQUISITE INFRASTRUCTURE AT AIRPORT AND SEAPORT OFFICES
The Committee agrees with the above suggestion and recommends that the Ministry of Health and Family Welfare should take initiative towards addressing the shortcomings forthwith in coordination with the Ministry of Civil Aviation at all seaports/airports handling import and exports of pharmaceutical products. The Committee will like to be informed of steps taken to address this problem. (Para 6.2)
NEW DRUGS APPROVAL
The Committee is of the view that due to untraceable files on three drugs, it is not possible to determine if all conditions of approval (indications, dosage, safety precautions) are being followed or not. Moreover the product monographs cannot be updated in the light of recent developments and regulatory changes overseas. Therefore all the missing files should be re-constructed, reviewed and monographs updated at the earliest. (Para 7.13) .............This matter needs to be reviewed to ensure safety of patients, fair play, transparency and accountability. (Para 7.14)
Unless there is some legal hitch, the Committee is of the view that there is no justification in withholding opinions of experts on matters that affect the safety of patients from public. Consideration should be given to upload all opinions on CDSCO website. (Para 7.15)
According to information provided by the Ministry, a total of 31 new drugs were approved in the period January 2008 to October 2010 without conducting clinical trials on Indian patients. The figure is understated because two drugs (ademetionine and FDC of pregabalin with other ingredients) were somehow not included in the list. Thus there is no scientific evidence to show that these 33 drugs are really effective and safe in Indian patients. (Para 7.16)
It is obvious that DCGI clears sites of pre-approval trials without application of mind to ensure that major ethnic groups are enrolled in trials to have any meaningful data. Thus such trials do not produce any useful data and merely serve to complete the formality of documentation. (Para 7.27)
The Committee recommends that while approving Phase III clinical trials, the DCGI should ensure that subject to availability of facilities, such trials are spread across the country so as to cover patients from major ethnic backgrounds and ensure a truly representative sample. Besides, trials should be conducted in well equipped medical colleges and large hospitals with round the clock emergency services to handle unexpected serious side effects and with expertise in research and not in private clinics given the presence of well equipped medical colleges and hospitals in most parts of the country in present times. (Para 7.28)
The Committee is of the view that taking into account the size of our population and the enormous diversity of ethnic groups there is an urgent need to increase the minimum number of subjects that ought to be included in Phase III pre-approval clinical trials to determine safety and efficacy of New Drugs before marketing permission is granted. In most western countries the required numbers run into thousands. However since the major objective in India is to determine the applicability or otherwise of the data generated overseas to Indian population, the requirement should be re-assessed and revised as per principles of medical statistics so that major ethnic groups are covered. A corresponding increase in the number of sites so as to ensure a truly representative sample spread should also be laid down in black and white. Furthermore, it should be ensured that sites selected for clinical trials are able to enroll diverse ethnic groups. For domestically discovered drugs, the number of subjects should be revised as well. This can be easily achieved by changes in the Good Clinical Practice (GCP) guidelines. (Para 7.29)
A review of the opinions submitted by the experts on various drugs shows that an overwhelming majority are recommendations based on personal perception without giving any hard scientific evidence or data. Such opinions are of extremely limited value and merely a formality. Still worse, there is adequate documentary evidence to come to the conclusion that many opinions were actually written by the invisible hands of drug manufacturers and experts merely obliged by putting their signatures........... Is the Committee mistaken in coming to the conclusion that all these letters were collected by interested party from New Delhi, Mumbai, Chandigarh and Secunderabad and handed over to office of the DCGI on the same day? If so, it is obvious that the interested party was in the loop in the entire process of consultation with experts. (Annexure 6)..............It is inconceivable that a letter dated 17-6-2005 from New Delhi will be delivered to the office of DCGI also in New Delhi after more than two months. The conclusion, as in aforementioned cases, is obvious. (Annexure 8) (Para 7.31)
If the above cases are not enough to prove the apparent nexus that exists between drug manufacturers and many experts whose opinion matters so much in the decision making process at the CDSCO, nothing can be more outrageous than clinical trial approval given to the Fixed Dose Combination of aceclofenac with drotaverine which is not permitted in any developed country of North America, Europe or Australasia. In this case, vide his letter number 12-298/06-DC dated 12- 2-2007, an official of CDSCO advised the manufacturer, Themis Medicare Ltd. not only to select experts but get their opinions and deliver them to the office of DCGI! No wonder that many experts gave letters of recommendation in identical language apparently drafted by the interested drug manufacturer. (Para 7.32)
In the above case, the Ministry should direct DCGI to conduct an enquiry and take appropriate action against the official(s) who gave authority to the interested party to select and obtain expert opinion and finally approved the drug. (Para 7.33)
Such expert opinions in identical language and/or submitted on the same day raise one question: Are the experts really selected by the staff of CDSCO as mentioned in written submission by the Ministry? If so how can they, situated thousands of miles away from each other, draft identically worded letters of recommendation? Is it not reasonable to conclude the names of experts to be consulted are actually suggested by the relevant drug manufacturers? It has been admitted that CDSCO does not have a data bank on experts, that there are no guidelines on how experts should be identified and approached for opinion. (Para 7.34)
The Committee is of the view that many actions by experts listed above are clearly unethical and may be in violation of the Code of Ethics of the Medical Council of India applicable to doctors. Hence the matter should be referred to MCI for necessary follow up and action. In addition, in the case of government-employed doctors, the matter must also be taken up with medical colleges/hospital authorities for suitable action. (Para 7.35)
There is sufficient evidence on record to conclude that there is collusive nexus between drug manufacturers, some functionaries of CDSCO and some medical experts. (Para 7.36)
On a more fundamental issue the Committee has come to the conclusion that when it comes to approving new drugs, too much is left to the absolute discretion of the CDSCO officials. There are no well laid down guidelines for determining whether consultation with experts is required. Thus the decision to seek or not to seek expert opinion on new drugs lies exclusively with the non- medical functionaries of CDSCO leaving the doors wide open to the risk of irrational and incorrect decisions with potential to harm public health apart from the possibility of abuse of arbitrary discretionary powers. (Para 7.37)
The Committee, therefore, strongly recommends that there should be non-discretionary, well laid down, written guidelines on the selection process of outside experts with emphasis on expertise including published research, in the specific therapeutic area or drug or class of drugs. Currently, the experts are arbitrarily chosen mainly based on their hierarchical position which does not necessarily correspond to the area or level of expertise. All experts must be made to file the Conflict of Interest declaration outlining all past and present pecuniary relationships with entities that may benefit from the recommendations given by such experts. The consulted experts should be requested to give hard evidence in support of their recommendations. (Para 7.38)
The Committee is of the view that responsibility needs to be fixed for unlawfully approving Buclizine, a drug of hardly any consequence to public health in India, more so since it is being administered to babies/children. At the same time the approval granted should be reviewed in the light of latest scientific evidence, regulatory status in developed countries, particularly in Belgium, the country of its origin. (Para 7.41) .........DCGI is expected to take action against those CDSCO functionaries who colluded with private interests and got the drug approved in violation of laws. The drug has since been banned by the Ministry for use in female infertility. (Para 7.42)
The Committee takes special note of this case of gross violation of the laws of the land by the CDSCO. First, in approving the drug for use in case of female infertility and thereafter, in exhibiting overt resistance in taking timely corrective steps despite very strong reasons favouring immediate suspension of use of letrozole for the said indication. Belatedly, the drug has been banned for use in female infertility. (Para 7.43)
The Committee is of the opinion that there must be some very good reasons for Danish Medicine Agency (Denmark) not to approve a domestically developed drug where an anti-depressant drug would perhaps be in greater demand as compared to India. Curiously, Deanxit is allowed to be produced and exported but not allowed to be used in Denmark. (Para 7.45)
The Committee feels that the DCGI should have gone into the reasons for not marketing the drug in major developed countries such as United States, Britain, Ireland, Canada, Japan, Australia just to mention a few. United States alone accounts for half of the global drug market. It is strange that the manufacturer is concentrating on tiny markets in unregulated or poorly regulated developing countries like Aruba, Bangladesh, Cyprus, Jordan, Kenya, Myanmar, Pakistan, and Trinidad instead of countries with far more patients and profits. Many of these developing countries are handicapped due to lack of competent drug regulatory authorities. Instead of examining and reversing regulatory lapses, DCGI has referred the matter to an Expert Committee to look at the isolated and restricted issue of “safety and efficacy” instead of unlawful approval in the first place. (Para 7.46)
The Committee recommends that in view of the unlawful approval granted to Deanxit, the matter should be re-visited and re-examined keeping in mind the regulatory status in well developed countries like Denmark, the country of origin; the United States, Britain, Canada, European Union and Japan etc. It is important to keep in mind that in Europe, there are two types of marketing approvals: Community-wide (cleared by European Medicine Agency) and individual regulators of member nations. EMEA is known to clear drugs after great deal of scrutiny while the competence and expertise of drug regulatory authorities of individual nations is not uniform and varies greatly from country to country. (Para 7.47)
The Committee recommends an enquiry into the said letter. The responsibility should be fixed and appropriate action taken against the guilty. The Committee should be kept informed on this case. (Para 7.49) The Committee takes special notice of this case of persistent insolence on the part of CDSCO and hopes that never again shall the DCGI approve drugs in violation of laws, that too for use in neonates and young children. (Para 7.51)
The Committee expresses its deep concern, extreme displeasure and disappointment at the state of affairs as outlined above. The Ministry should ensure that the staff at CDSCO does not indulge in irregularities in approval process of new drugs that can potentially have adverse effect on the lives of people. It is difficult to believe that these irregularities on the part of CDSCO were merely due to oversight or unintentional. Hence all the cases listed above and cases similar to these should be investigated and responsibility fixed and action taken against erring officials whether currently in service or retired. (Para 7.52)
DRUGS WITHDRAWN/DISCARDED/BANNED ABROAD
The Committee has noted that there are a very large number of alternative analgesics, antipyretics in the Indian market. With so many countries banning Analgin, not to mention unlawful over-promotion by manufacturers, the CDSCO should be directed to re- examine the rationality of continued marketing of Analgin. (Para 8.4)
It is to be kept in mind that a drug becomes a candidate for withdrawal not only due to serious side effects but also when safer, more efficacious drugs are launched. Unfortunately, no attention is being paid to this issue. This principle should apply to all cases and all drugs need to be evaluated periodically. (Para 8.5)
The documents submitted by the Ministry show that even in large developed countries with well developed drug regulation such as US the adverse reactions are not detected by spontaneous reports from doctors in practice. All major side effects were detected in large scale controlled, focused Post-Marketing Phase IV trials involving thousands of patients such as SCOUT on anti-obesity drug sibutramine (now banned) and the RECORD trial on rosiglitazone (now banned). Therefore to expect that any spontaneous reports from medical profession, either in private practice or even institutions (medical colleges, large hospitals) will pick up hitherto unknown side effects in India is not realistic. There is hardly any alternative but to take immediate cognizance of serious adverse drug reactions reported from countries with well developed and efficient regulatory systems. The health and lives of patients in India cannot be put to risk in the hope of detecting ADRs within the country. (Para 8.7). The Committee feels that since the chances of picking up unknown serious adverse effects of drugs being marketed in the country are remote, therefore CDSCO should keep a close watch on regulatory developments that take place in countries with well developed regulatory systems in the West and take appropriate action in the best interest of the patients. (Para 8.8)
In most cases, most of these experts whether appointed by CDSCO or DTAB are from Delhi. The following facts reveal this pattern:
1. Rimonabant was referred to a committee of six experts, all from Delhi.
2. Levonorgestrel: Four out of five from Delhi.
3. Letrozole: Four out of five from Delhi.
4. Sibutramine: All five from Delhi.
5. Rosiglitazone: All five from Delhi.
6. A review of membership shows that one expert sat on 5 of the 6 committees.
One wonders whether expertise on drugs is confined to Delhi. (Para 8.10)
The Committee strongly recommends that with some 330 teaching medical colleges in the country, there are adequate number of knowledgeable medical experts with experience who can be requested to give their opinion on the safety and efficacy of drugs. The need is to make such consultations very broad based so as to get diverse opinion. The opinions, once received, can be put in public domain inviting comments. Once the experts know that their opinions will be scrutinized by others, including peers, they would be extra cautious and give credible evidence in support of their recommendation. (Para 8.11)
FIXED DOSE COMBINATIONS (FDCs)
Unfortunately some State Drug Authorities have issued manufacturing licenses for a very large number of FDCs without prior clearance from CDSCO. This is in violation of rules though till May 2002, there was some ambiguity on powers of the State Drug Authorities in this respect. However the end result is that many FDCs in the market have not been tested for efficacy and safety. This can put patients at risk. (Para 9.2)
To remove such unauthorized FDCs from the market, the Central Government can either issue directions under Section 33P to states to withdraw the licences of FDCs granted without prior DCGI approval or the Central Government can itself ban such FDCs under Section 26A. (Para 9.3)
The Committee was informed that DCGI has been requesting State Orug Authorities not to issue manufacturing licences to new FDCs and suspend licences of unauthorized FDCs issued in the past. However in exercise of powers under Section 33P specific directions have not been issued. The Ministry failed to provide any coherent reason for lack of action under this Rule. The Ministry informed the Committee that even if Section 33P was invoked, there was no provision to take action against States if directions were not carried out. If considered necessary, the Ministry may examine the possibility of amending the law to ensure that directions under Section 33P are implemented. (Para 9.4)
It is also possible to ban FDCs, not authorized by CDSCO by invoking Section 26A which empowers the Central Government to ban any drug to protect public health. The Committee was informed that the Government has not evoked Section 26A either so far. No explanation was offered for not using powers under Section 26A. (Para 9.5)
The Committee was informed that the issue regarding grant of Manufacturing Licenses for unapproved FDCs by some State Drug Authorities were first deliberated in 49th DTAB meeting held on 17 February, 2000 i.e. 11 years ago. It is a matter of great concern that even after a lapse of a decade, no serious action has been taken. (Para 9.6)
The Committee is of the view that those unauthorized FDCs that pose risk to patients and communities such as a combination of two antibacterials need to be withdrawn immediately due to danger of developing resistance that affects the entire population. (Para 9.7)
The Committee is of the view that Section 26A is adequate to deal with the problem of irrational and/or FDCs not cleared by CDSCO. There is a need to make the process of approving and banning FDCs more transparent and fair. In general, if an FDC is not approved anywhere in the world, it may not be cleared for use in India unless there is a specific disease or disorder prevalent in India, or a very specific reason backed by scientific evidence and irrefutable data applicable specifically to India that justifies the approval of a particular FDC. The Committee strongly recommends that a clear, transparent policy may be framed for approving FDCs based on scientific principles. (Para 9.8)
DRUGS ADVISORY COMMITTEES
The Committee feels that though the Ministry is forming DACs, which are given very important powers, there is no transparent procedure for the selection of experts of such Committees. The Committee also recommends that institutions from which experts are chosen should be from different parts of the country. (Para 10.2)
SIMILAR BRAND NAMES
The Committee strongly recommends that all such cases should be thoroughly reviewed in close coordination with State Drug Authorities. Specific procedures may be framed for approval of brand names. The procedure adopted by the Registrar of Newspapers to avoid duplication may be worth emulating. As a beginning, a data bank of all branded pharmaceutical products along with their ingredients should be uploaded on the CDSCO website and regularly updated. (Para 11.2)
In order to scrutinize the compliance of this rule, the Ministry was asked to furnish PSURs in respect of 42 randomly selected new drugs. Since files in respect of three drugs were reportedly missing, PSURs should have been supplied for the balance 39 drugs. The Committee is, however, constrained to note that PSURs in respect of only 8 drugs were submitted by the Ministry. The Committee was informed that 14 drugs though approved were not being marketed or were launched lately and hence PSURs would be expected later. There was no explanation for not submitting PSURs in respect of rest of 17 drugs. (Para 12.2)
Out of 14 drugs that were reported to be either not yet launched or lately launched, the Committee discovered that, at least, two products (FDC of glucosamine with ibuprofen; and moxonidine) were indeed in the market for some time and concerned manufacturers should have submitted PSURs. But the Committee has not been given any explanation for
non-submission of PSURs for these two drugs. (Para 12.3)
The Committee observed that even, in those cases where the PSURs were submitted, the frequency and/or format was not as per rules. In the case of two drugs of MNCs (dronedarone of Sanofi Aventis and pemetrexid of Eli Lilly), the PSURs were neither India specific nor in the approved format as required by law. Some companies submitted PSURs for the products being marketed in the country but very few PSURs were India-specific. (Para 12.4)
The Committee is of the firm view that there is a poor follow-up of side effects in Indian patients both by doctors and manufacturers. The objective of PSURs is to collect information about adverse effects on patients in India which would help to determine ethnic differences, if any and result in dosage adjustment, revision of precautions and warnings, if necessary. The Committee takes strong exception to such rampant violation of the mandatory requirements. (Para 12.5)
The Committee strongly recommends that the Ministry should direct CDSCO to send a stern warning to all manufacturers of new drugs to comply with mandatory rules on PSURs or face suspension of Marketing Approval. PSURs should be submitted in CDSCO-approved format which would help track adverse effects discovered in Indian ethnic groups. (Para 12.6)
The Committee feels that the conventional system of locating side effects through spontaneous reporting by doctors to either drug companies or drug regulators has been found to be unsatisfactory. The most effective system is by controlled post-marketing Phase IV studies on a very large number of patients. In the past decade, all the major adverse effects that led to banning of drugs were identified in large scale Phase IV trials. The Ministry may wish to consider the possibility of using this format in the country. (Para 13.3)
UPDATION OF INFORMATION ON MARKETED DRUGS
The Committee feels that unless information on marketed drugs is continuously updated, there is risk of irrational or inappropriate use of medicines putting patients at risk. The Committee, therefore, recommends that immediate steps need to be taken to address this issue. The CDSCO should be directed to continuously update monographs based on information from regulatory authorities the world over. (Para 14.3)
A drug can be categorized ‘Not of Standard Quality’ for a variety of both major and minor technical reasons such as not stating the name of the pharmacopoeia correctly, problem with quality of bonding agent, colouring agent, dissolution time, etc. However, there are other more serious cases, where the active ingredient is significantly less in quantity that can harm patients. Therefore, this problem needs to be addressed with all the seriousness that it deserves both by more rigorous checks in procuring bulk drugs (particularly from developing countries with not so stringent quality checks and export controls) and by in-house quality control by manufacturers or solving the problem in transportation and/or storage at Distribution/retail levels. (Para 15.4)
By the time a sample is tested, a large number of packs get sold out with undeterminable injury to patients. There is no effective method of recalling unsold stocks lying in the distribution network. This cannot be allowed to go on. (Para 15.5)
The Committee feels that there should be severe punishment for manufacturing and for allowing sub-standard drugs to enter the distribution chain. Products with severe deficiencies should be penalized the same way as producers of spurious drugs by amending rules. There is also a case to incorporate penal provisions for manufacturing misbranded and adulterated drugs. (Para 15.6) It is known that retail chemists also stock and sell items other than drugs including chocolates, cold drinks etc. During summer these items are stored in the refrigerator while due to paucity of space temperature-sensitive medicines may be lying outside. When samples are picked up, tested and found to be sub-standard, the State Drug Authorities blame and prosecute manufacturers. Therefore the Committee recommends that specifically in the case of temperature sensitive products such as insulins, due consideration should be given to the reference samples of the same batch preserved by the manufacturers. (Para 15.7)
The Committee is extremely anxious on both counts: such hugely costly imported drugs losing their potency before use and the possibility of fakes entering the chain. It is strange that multinational drug companies that have well staffed marketing offices in India, instead of importing drugs from their overseas affiliates and selling them are using traders to handle this activity. Apart from risk to patients, there is leakage of revenue to income tax. While the promotional expenses on imported formulations are being paid by the Indian branch of MNCs thus reducing income tax liability, there is no corresponding income since traders are paying directly to overseas offices of MNCs. The Committee would like the Ministry to ensure that in cases where MNCs have offices in India, traders are not permitted to import formulations of such companies. The Committee would like to be kept informed of the steps taken on this issue. (Para 15.9)
The Committee recommends that once a batch of a drug is found to be sub-standard and reported to CDSCO, it should issue a press release forthwith and even insert paid advertisements in the newspapers apart from uploading the information on the CDSCO website. Retail chemists should be advised to stop selling unsold stocks and return the same to local Drugs Inspectors as per rules. The Committee understands that at least two State Drug Authorities, that of Maharashtra and Kerala, have taken the initiative to upload information on spurious and sub-standard drugs on their websites on a monthly basis. These are welcome measures worth emulating by other states and the Centre. (Para 15.11)
ADVERTISING OF PRESCRIPTION DRUGS IN THE LAY MEDIA
The Committee would like the Ministry to take appropriate action against the companies that have advertised the above Schedule H drugs in the lay press. The provisions in the Drugs and Magic Remedies Act are not stringent enough with the result that manufacturers violate them at will. It also recommends that apart from giving sharper teeth to the Drugs and Magic Remedies Act, a provision should also be incorporated in the Drugs and Cosmetics Rules to ban such practices and penalize offenders. The Committee would like to be informed of the action taken to implement these recommendations. (Para 16.2)
The Committee is of the firm opinion that accurate information on drugs for patients is absolutely essential to prevent inappropriate use more particularly in children, elderly, during pregnancy and lactation. The Committee recommends that the matter may be looked into to ensure that consumers have the required information to use medicines safely. Given
the widespread internet connectivity, it is advisable to devise a system where patients can get unbiased information on drugs at the click of the mouse in any language. (Para 17.3)
CLINICAL TRIALS ON NEW DRUGS
Due to the sensitive nature of clinical trials in which foreign companies are involved in a big way and a wide spectrum of ethical issues and legal angles, different aspects of Clinical trials need a thorough and in-depth review. This Committee has, accordingly, taken it up as a subject for detailed examination separately under the heading ‘Clinical Trials of
Drugs’. (Para 18.2)