A Conference on Guideline Standardisation (COGS) was convened in April 2002 ‘to define a standard for guideline reporting that would promote guideline quality and facilitate implementation’ (Shiffman et al., 2003).

Twenty-three people with expertise and experience in guideline development, dissemination and implementation participated. Representatives of 22 organisations active in guideline development reviewed the proposed items and commented favourably.

Closely related items were consolidated into 18 topics to create what they called the COGS Checklist. (Shiffman et al., 2003). These items are:

A careful look at the items reveals the comprehensive nature of this Checklist. Each item needs more than cursory perusal by those interested in salvaging CPGs from ulterior influence. Please do not just skim through them. Read and discuss how each item is important, so they register and maybe you may add a few to them yourself.

It includes items for standardization (Items 5,6,8,9,10), conceptual issues (Items 2,3,13,14), up gradation (Items 1,12,18), conflict of interest (Items 6,7), patient interest (Items 4,5,11,15,16,18) and systematization (Items 4,8,9,10,13,14,17,18). Even items for individual preferences, choice or values are not neglected (Item 16). Special mention must be made of Items 6 and 7, which specify disclosure of conflict of interest both in the Developer (including the organization that develops and the individuals involved in the guideline's formulation), as well as in the sponsor or funding source (and its role in developing and/or reporting the guideline). All salutary moves.

Another significant contribution of this checklist is its prospective use:

In contrast to other instruments that have been developed for post hoc evaluation of guideline quality, the COGS checklist is intended to be used prospectively by developers to improve their product by improving documentation (Shiffman et al., 2003).

Also, it is the result of a consensus standard for prospective development of quality CPGs:

Although many individual organizations have devised manuals and procedures for developing guidelines, we are unaware of any consensus standard that has been proposed for use prospectively to promote the development of high-quality guidelines (Shiffman et al., 2003).

The paper rightly ends with a call to overcome roadblocks in CPG use by carrying on a ‘sustained’ and ‘productive’ discussion amongst all the parties involved: developers, disseminators, implementers and ‘knowledge managers’ of guidelines:

A sustained and productive discussion among guideline developers, disseminators, implementers and knowledge managers about critical guideline items and clear statement of decidable and executable recommendations will help to overcome major impediments to guideline use (Shiffman et al., 2003).

This comes to attention as one studies the conflicting recommendations of CPGs and Drug review panels. This is the case in Canada, but similar problems must arise in other places too. An interesting rather recent such disparity was in 2003 and reported in an Editorial of the CMAJ (CMAJ, 2005). It is worth a small elaboration here.

An expert committee of the Canadian Diabetes Association (CDA) responsible for laying down CPGs recommended that, for treatment of Type I and Type II Diabetes patients where there were problems of fasting hypoglycemia and/or problems controlling fasting plasma glucose, a new long acting insulin, insulin gargline, be used in preference to generic long-acting insulin in use till date (Canadian Diabetes Association Clinical Practice Guidelines Expert Committee, 2003). In 2005, members of the Common Drug Review (CDR), a Canadian national advisory process that evaluates drugs for provincial formularies, recommended that the drug not be listed (CMAJ, 2005; Canadian Coordinating Office for Health Technology Assessment, 2005). ‘Both groups of experts evaluated virtually the same evidence from about 20 randomized controlled trials’ (CMAJ, 2005).

The Association sponsored CPG recommends a drug. The Drug Review Panel rejects the same drug. Both come to their conclusions from the same set of clinical trials. How is that possible?

The CDA guidelines did not disclose whether members of their expert panel had financial or other interests linked with manufacturers of the preferred insulin gargline. But the CDA was quick to refute CDR's recommendations against insulin gargline. They sent an open letter to provincial ministries of health (addressed to the health minister) expressing concern with the CDR recommendation (Canadian Diabetes Association, 2007). Also worth noting here is the fact that insulin gargline is three times costlier than generic long-acting insulin. (The above quoted editorial mentions five times, but they corrected themselves later.)

That same editorial quotes a recent report on more than 200 guidelines (from various countries) deposited in 2004 with the US National Guideline Clearinghouse, which found that “more than one third of the authors declared financial links to relevant drug companies, with around 70% of panels being affected.” (Taylor and Giles, 2005). It goes on to make a piquant comment:

This controversy over guidelines is not unique to those developed by the CDA. There has been similar debate regarding the management of hypertension, where national guidelines recommend expensive patented drugs over proven generic compounds. Almost all consensus and guideline development panels are supported by pharmaceutical companies with vested interests and many panelists receive research grant support and personal compensation for lectures and advice from the same companies… To maintain that such financial conflicts exert no influence on panelists' recommendations is to ignore accumulating evidence that they do. A national guideline recommendation encumbered by money in the form of lecture and consulting fees, stocks, options, patents and royalties may be effective in increasing sales and profits for companies, but may also be harmful to patients. And it will almost always result in higher-cost drugs being prescribed. (According to the CDR, insulin glargine costs 5 times as much as generic long-acting insulin^*.) (CMAJ, 2005)

Before we jump to the conclusion that this is another clear case of manipulation by pharma, let us also look into an argument presented cogently by one who has been on both panels, a CPG and a Drug Review Panel. Phil McFarlane, from the Division of Nephrology, St. Michael's Hospital, Toronto, Ontario, Canada, is ‘one of the few physicians who have served on both clinical practice guideline groups and drug review panels (in his case the CDA and Canadian Hypertension Education Program [CHEP] guideline groups and the Ontario Drug Programs Branch Pharmacoeconomic Review Committee respectively) (McFarlane, 2006). This is what he has to say:

The mandate of guideline groups and drug review panels differ so extensively that one should expect that their respective conclusions will often differ. Guideline groups advocate use of the most effective therapies as suggested by the medical literature and typically do not perform economic analyses when generating guidelines. Drug review panels determine whether a new therapeutic is sufficiently cost-effective and has an acceptable budget impact within the context of their jurisdiction (McFarlane, 2006).

He then goes on to list four primary reasons why guidelines do not and in his opinion should not, carry out economic analyses:

First, guideline groups do not have a mandate from any provincial or federal agency to make decisions about what therapies will be publicly funded. Equally important, they have no mandate to recommend removal of currently funded therapeutics when the cost-effectiveness of care would benefit from such an action. Second, guideline groups are not provided projected budget information that would help inform an economic assessment. Third, one could consider an assessment of effectiveness to be somewhat “universal.” In contrast, the determination of whether a therapy is acceptably cost-effective can certainly vary between jurisdictions. Finally, an economics based approach would place guideline groups in a true conflict of interest between their patient advocacy role and their obligations to the health care payors (McFarlane, 2006).

The mandate of guideline groups and drug review panels differ so extensively that one should expect that their respective conclusions will often differ. Guideline groups advocate use of the most effective therapies as suggested by the medical literature and typically do not perform economic analyses when generating guidelines. Drug review panels determine whether a new therapeutic is sufficiently cost-effective and has an acceptable budget impact within the context of their jurisdiction (McFarlane, 2006).

In essence, this means Guideline groups look into the most effective therapies, Drug review panels look into the most cost effective therapies. Which means we realize and accept, that the most therapeutically effective may not necessarily also be the most cost effective. And the most cost effective may not necessarily be the most therapeutically effective. In the context of effectivity, cost should not act as a constraint, especially when as important an issue as therapy and potential morbidity and mortality are involved. Therefore, it makes sense to allow Guidelines groups to do their job. However, it is equally important cost effectiveness be looked into, since spending is an issue, especially for statutory and federal authorities. So, it makes sense for them to carry out cost calculations and determine most cost effective therapies, which they do with their Drug Review Panels. So, the prescribing doctor writes the CPG recommended most effective treatment when cost is not a constraint. And writes the CDR recommended one when it is.

And how unequivocal are their findings?

To find an answer to this, consider the following. What happens when the results of these trials are manipulated, the methodological rigour reported is more on paper than in practice and the unequivocal findings are based on fudged figures at industry centers rather than in academic setups? Since many of the latter are only too happy to hand over findings to industry personnel to do as suits them, as long as publication in a prestigious journal is arranged? What happens when the CPG panelists themselves face a major conflict of interest, being in financial compromise with the very companies whose products are being considered? What do we make of the fact that most CPGs recommend products that belong to the companies sponsoring the CPG panelists?

Here is the problem. And a big one at that.

But this problem can be conveniently resolved by a simple step. By making CPG panelists go into cost effectiveness along with recommending Guidelines. What then happens is that they have to consider not only effectiveness but also costs. Now effectiveness can be fudged, cost cannot. Why? Because, what is the cost is well known. When Guidelines are recommended and they are graded according to whether they are Most, Moderately or Least Cost Effective, some very salutary processes are set into motion.

Panelists cannot neglect the cheaper alternatives under the pretext of effectivity. Panelists cannot tout the most recent as the most effective, as often they are markedly costly compared to the earlier. And they will have to say this in so many terms. In fact that is the reason newer Guidelines are a flourishing academic activity. Panelists will then have to get themselves funded for their fringe, and other, benefits by the most cost effective, if at all. And that is hardly likely to work, for they will not then remain cost effective. (There is of course the danger that the most cost effective will attract such self-seekers. But in trying to pamper the latter, they may no longer remain cost effective. So they will be forced not to cater to the panelists’ interests to protect their own).

There are 4 primary reasons why guideline groups do not (and in my opinion should not) perform economic analyses when generating guidelines. First, guideline groups do not have a mandate from any provincial or federal agency to make decisions about what therapies will be publicly funded (McFarlane, 2006).

This situation can be countered by simply giving them such a mandate. What if they had such a mandate? Would they carry out such a cost benefit analysis? This is a question which needs a serious answer. Our hunch is they would say no for a variety of reasons meant to camouflage the most important one which will never be mentioned: the commercial interest of sponsors. One sometimes feels why don't the guys make a clean breast of it and end this whole debate? Just say: yes. We have, and need, sponsors. We cannot neglect their commercial interests. We must include the prominent sponsor's product in our guidelines. So what's your problem? If you have objections, go raise them at whatever forum and suit yourself. End of debate.

Well and truly, debate would just end. But something salutary would start. The lid would be off the whole can of worms.

Just think of it another way. If you, or we, had to pay for a certain therapy, would we not want to have an informed opinion on which is the most cost effective? Should the fact that they have/don't have such a mandate from any provincial or federal agency be the only reason why a cost-benefit analysis need be carried out? Let us not kid ourselves. Somebody is paying for somebody using the recommended guideline. Why can that individual/agency not have the most cost-effective remedy spelt out?

This would be laudable if therapies were recommended solely because of their intrinsic therapeutic worth. That would happen only if guidelines developers were not conflicted in their interests and considered the benefits of a certain recommendation without favour and only after a careful appraisal of research evidence of the clear cut effectiveness of a certain recommended therapy as against one which is not. What evidence is given weightage is very important here. When that itself is liable to manipulation, when newer therapies are projected better not in comparison to older therapies but as compared to placeboes, what other method of control remains except to consider cost effectiveness? It is a tragedy that the only evidence that has remained objective is not scientific evidence but the cost factor. You should not be able to, but unfortunately can, manipulate scientific evidence. You cannot manipulate declared cost, which is for all to see. Well, smart operators will manipulate that as well, when they calculate how cost is not just money, but also time, smoothness of the procedure, distress etc. But that can be seen through by the rights-conscious market savvy patient of today. So, we really have no option today but to include cost dynamics in guideline recommendations.

What does that mean? Have they ever demanded the mandate to 'recommend removal of currently funded therapeutics when the cost-effectiveness of care would benefit from such an action’? Now or ever? What prevents them from making such a demand explicit? Why this is important is because when cost effectiveness becomes an important feature to remove current therapy, it becomes equally important, by default, an important reason to approve new therapy. And therein lies the rub. It is important, therefore, that those involved in laying down new/updated CPGs be given the mandate to 'recommend removal of currently funded therapeutics when the cost effectiveness of care would benefit from such an action’ as much as given the mandate to recommend inclusion of a new therapy only when the cost effectiveness would benefit from such an action.

Why? Because, such cost calculation automatically helps to keep a check on cost escalation and all the questionable activities it can help spawn. It also helps CPG panelists keep to the straight course. And it also helps treating physicians and their patients benefit from such cost calculation.

It is imperative that treating physicians and paying patients know the costs that therapy involves. And if a newer one is low on the cost effectiveness scale, the physician is well aware of the same and recommends treatment accordingly. As it happens, physicians may not ordinarily make such calculations while recommending treatment, implicitly assuming that the more costly, the better. A reflection of the same is the attitude of the patient/care giver who reassures his physician not to bother about costs, but carry out treatment, however costly it may be. Now, we know, some patients/caregivers are only reassured if the costliest therapy is given, even if they may not afford it. That is to quell any subsequent guilt feelings that the ‘best’ was not given simply because it was costly. But if the costly is not really the best, is it not the duty of the treating physician to make it explicit? And how, pray, will he ever make it explicit if he himself is not aware of the costs and benefits involved, which experts can, and should, guide him about? So, while he is open to new therapies, the hype over new treatments does not carry him away?

If he keeps to the straight and narrow path, and if his CMEs allow him to, what really would happen is, he would prescribe the best possible treatment at the most cost effective rates. But to do so, he himself should have carried it out. And for him to carry it out, the smart alecks who carry out his CMEs should carry it out and present it as such. For them to do so, the smarter alecks who lay down CPGs must carry it out. However, if they do, they are hardly likely to forward the profit welfare agenda of their sponsors. So, the convenient method is not to involve CPGs in any cost benefit analysis at all. Just leave it to the discretion of individual practitioners who will conveniently err on the cost escalation side to appear more informed. Or expect the governmental and other statutory bodies to carry out such cost effective analysis. But that is hardly likely to influence the great mass of prescribers. Firstly, because they may hardly know about it, since the visibility/credibility of such analysis is low compared to the marketing and ‘evidential’ pressures of the smart alecks. Secondly, because to go by the cost effective guidelines may hardly be the in, or fashionable, thing to do. So the smart alecks manage to set and dictate the agenda, and do so on ostensibly justified scientific grounds: that CPGs do not, and should not, have the mandate or the necessity to carry out cost benefit analysis.

Second, guideline groups are not provided projected budget information that would help inform an economic assessment (McFarlane, 2006).

Indeed they are not. But do they ask for budget information? Now let us ask this question. If Guidelines were not provided with evidence based research studies, would they work? Obviously not, because they consider that integral to their work. If they were to consider cost benefit analysis as important to their work as research evidence, they would refuse to work in the absence of such budget information. Admitted, they may not be experts in such an analysis. They need not be. They could have on their committee someone who is. In fact, an expert who carries out cost benefit analysis of every Guideline recommendation should be an integral part of the committee. He brings in the economic dimension, while the other experts bring in the medical. It is of course best if the medical expert is also an expert economic analyzer, but that is expecting a little too much in every case. In the circumstances, such an expert will carry out his economic analysis. The whole committee can then deliberate over all issues - fresh evidence available, costs involved and intended beneficiaries of such CPGs.

They may then do well to lay down the following:

What happens at present is very convenient. The manufacturer funds experts for their activities. The experts sit on committees and recommend their products. The consumer is not offered any cost analysis but impressive portrayals in seminars and journal articles. So the costly new process gets acceptance. And milks patients and payers till a new process can be found to milk them further.

Now, it does not mean there is no benefit with the present procedure. If that were so, the game would have been exposed by now already. And we would have no need to write pages over it. It is just that the benefits are not commensurate with the costs involved. And, to keep the game under wraps, perceptions are adroitly changed. What appeared the most promising till yesterday is suddenly found full of faults today. It falls out of favour, for a new star comes on the ascendant. We have detailed this game before (Singh and Singh, 2003). And prescribers and beneficiaries (patients) get taken for a ride. We do not suggest cost benefit analysis is the panacea to this problem. But it will be one important step forward to stem the rot.

However, let's not forget that it will meet with great, and apparently justified, resistance. For the forces that will not get a chance to play their game know exactly what this means. They will present arguments how it is not in the benefit of biomedical research or patient welfare for experts to carry out cost analysis. That's for caretakers to decide, they would say. To this we have only one answer. If they themselves were to fall sick and had to pay for their treatment, would they not want to think of the most cost effective therapy for themselves? If a Guideline does that for them, would they not thank medical practice and its practitioners that such care is indeed taken?

Third, one could consider an assessment of effectiveness to be somewhat “universal.” In contrast, the determination of whether a therapy is acceptably cost-effective can certainly vary between jurisdictions (McFarlane, 2006).

Therapeutic effectiveness is ‘universal’ in a way, cost effectiveness and its acceptability is variable for different socio-economic and geographical areas. Agreed. Even then, let guideline layers lay down cost effectiveness in their geographical area of work. And match it with their judgement of universal effectiveness. Other workers at other places will study whether cost effectiveness as presented by the guidelines layers is equally applicable in their place. In barring a few cases, it is likely to be the same. How can the author say it can certainly vary? One has to carry out research to find out if it does. All one can say is it is likely to vary.

This game must stop. For, it has very negative implications for patient welfare, patient confidence in biomedicine and future progress of biomedicine itself. Moreover, because of such games playing, the brighter minds that get into biomedical research have an alternative to progressing, apart from the straight and narrow path. And if such an alternative promises faster and easier returns, these brighter minds can gradually get persuaded to accept it as legitimate. This cannot but compromise the genuine progress of biomedical research. Also, patients’ confidence in therapy is likely to reduce and the inevitable suspiciousness of therapists’ intentions, resultant patients’ right activism and consequent legal tangles likely to increase. Alternatives to mainstream medicine are also likely to appear more attractive. All in all, chances are a number of serious road-blocks will hamper the forward march of this otherwise very useful and promising branch.

Finally, an economics based approach would place guideline groups in a true conflict of interest between their patient advocacy role and their obligations to the health care payors (McFarlane, 2006).

This point needs elaboration. It means guideline groups will develop a conflict of interest if they consider cost effectiveness. Their basic loyalty is towards patient welfare and if they have to consider cost effectiveness, they may be forced to recommend less effective therapies just because they are less costly. And purely to satisfy people who pay for the health care.

It is important to recognize that the quality of the health economics section of a company's approval application could be lower than the clinical section, which could affect the subsequent conclusions about the drug (McFarlane, 2006).

While this may indeed be true, it need hardly detain us, because we are not concerned with the quality of the health economics section of a company, nor that of its clinical section. We are concerned with guideline groups themselves doing the effective and cost effective analyses. A company's application and its expertise has nothing to do with, or at least need have nothing to do with, what guideline groups conclude, unless of course both overlap. And woe betides biomedicine if they do.

The conclusion needs to be looked into:

The roles of guideline groups and drug review panels are both necessary and complimentary. Recognizing that the most effective therapies will not always be the most cost-effective leads to the appropriate expectation that guideline groups and drug review panels may reach opposite conclusions (McFarlane, 2006).

Indeed, it's true sometimes the most effective may not be the most cost effective. We would like to know why? Is it because the raw material and the processing is costly or is it because the drug/devise has to make the billions before it runs out of steam? This is a critical exercise, especially for the well-wishers of biomedical advance, who may be convinced by the above-mentioned argument. And in light of the conflicted interests involved, we think it is necessary that guideline groups also do cost analysis to salvage themselves. We think they need to reveal their conflicts of interest fully and desist from taking part if they are conflicted. They need to also resist any attempts to approve costly newer unproved therapies under the guise of effectivity. This they can do by considering and laying down most, moderate and least cost effective amongst the various prevalent therapies as of date.

Hence, it is necessary for guideline groups to find the most effective and also the most cost effective, of therapies and therapeutic clusters and to give reasons why they consider them such.

The reason CEDAC recommended against reimbursement was that the relatively small improvement in hypoglycemia was not felt to justify the drug's more than 3-fold price relative to NPH (neutral protamine Hagedorn) insulin (Laupacis, 2006).

There it is, in black and white. A small improvement true, but not warranting recommendation of a three fold costlier drug. Now, the CDR did it and we now know what to do. If the Guidelines members had realized it and brought it to the notice, how would it have harmed informed decision-making? Of course that it would possibly harm economic interests of sponsors and related agencies, including those sponsored, is a possible hidden agenda. The reason why cost is kept out of calculations now becomes explicit.

He goes on to say further, referring to minimization of bias in CPGs and Associations which sponsor it:

Clinical practice guidelines and reimbursement recommendations such as those of the Canadian Diabetes Association (CDA) and the Canadian Expert Drug Advisory Committee (CEDAC) about insulin glargine have a potentially great effect on clinical practice. Minimizing bias during their development is therefore at least as important as it is during clinical trials. A conflict-of-interest guideline is only one method of minimizing bias (Laupacis, 2006).

CEDAC members are appointed by federal, provincial or territorial deputy ministers of health and are paid an honorarium by the CDR; public-drug-plan managers are allowed to observe CEDAC meetings; and CEDAC has no formal interaction with members of the public. In addition, CEDAC reports to the Board of the Canadian Coordinating Office of Health Technology Assessment (CCOHTA), which is made up entirely of representatives of the federal/provincial/ territorial Ministries of Health. No wonder a recent external assessment of the CDR found that members of advocacy groups representing people with various diseases called for greater public involvement in the CDR process. On the other hand, the CDA guidelines were sponsored by pharmaceutical and diagnostic companies, the methods of reviewing and summarizing the literature were not fully described and the potential conflicts of interest of authors are unknown (Laupacis, 2006).

CEDAC members, who talk of cost effectivity, are paid known amounts as honoraria. CDA Guidelines, which talk of effectivity, are sponsored by companies, their method of reviewing/summarizing literature are not clarified, their conflicts of interest not revealed and a drug three fold costlier is recommended. Does it take any great effort to read between the lines as to what this signifies?

This is the game we have to carefully expose and doggedly prevent from recurring.

Neither the guidelines nor the CDA letter of protest to the Canadian Ministers of Health about CEDAC's recommendation acknowledged the 3-fold price differential associated with insulin glargine compared with NPH insulin (Laupacis, 2006).

Isn't it obvious why it should be so? A statement such as this would weaken their case irreparably. And when you are part of an advocacy group, you advocate, you adopt a beneficial stand, you do not try to get to inconvenient truths.

No wonder those who pay for drugs are concerned that groups such as the CDA sometimes preferentially emphasize the evidence that supports their position and minimize the evidence that does not (Laupacis, 2006).

Emphasising evidence that supports and minimizing evidence that doesn't is advocacy at its best. And while it may suit the interests of those espoused, it is a moot point whether it serves the interests of biomedical advance and patient welfare, under which umbrellas all acts of omission and commission get carried out.

Interpreting the literature is not the same as summarizing it: interpretation inevitably incorporates an individual's values and perspectives. CEDAC's mandate is to make reimbursement recommendations from the perspective of the health care system, based not only upon a drug's effectiveness but also its cost-effectiveness (Laupacis, 2006).

Such should be the mandate of most, if not all, reimbursement systems. And paying for self-treatment systems as well. And we may add that till enough safe guards are in place with regard to CPGs, the one process that pre-empts much unfair means is calculation of cost-effectiveness by guideline layers themselves, which can be verified by bodies like CEDAC in particular and CDRs in general. What applies in this case in Canada is applicable in its essentials across other geographical areas.

I believe that the CDR process of reviewing and interpreting the available literature is as unbiased as possible (Laupacis, 2006).

While this is laudable, how much better would it be if we could say the same about Association CPG processes of reviewing and interpreting available literature? But to be able to say that, a thorough cleansing of the system and placing appropriate checks and balances in place, is obligatory.

However, AGREE itself requires some detailed work up by the individual clinician. Again a daunting task for most. For most clinicians neither have the aptitude, not the ability, to scale up the knowledge pyramid of burgeoning contemporary biomedical literature (scaling the knowledge pyramid, a phrase used by Davis et al, 2006). So what do we do? To facilitate this process occurs, a body like the GAC (Guidelines Advisory Committee) applies the AGREE criteria to individual guidelines and rates and endorses the best possible guideline (GAC, 2007).

Such an initiative needs to be duplicated at other places (this being an Ontario, Canada, initiative), in other countries, so guidelines remain less conflicted and become more relevant to local needs. What, however, must also be ensured is that CAG members and those of like bodies, do not themselves remain conflicted. An enlightened clinician-consumer, who keeps himself abreast of relevant literature from proper sources, is the greatest insurance against conflicted individuals taking biomedicine for a ride. By relevant literature we mean literature apart from pharma rep pamphlets and CMEs speeches. Proper sources include reading what those concerned with maintaining ethical standards in biomedicine write. As well as the write-ups of medical journalists.