(*) המחבר הוא אנליסט פארמה בכיר בברנשטיין השקעות, ניו יורק
מטרת המאמר היא להעלות את המודעות בפני הקהילה הרפואית ומקבלי ההחלטות בשוק הבריאות בישראל ליתרונות המשמעותיים של אימוץ מהיר ונרחב של תכשירים ביוסימילאריים בישראל.
להערכתנו, שינוי במדיניות לכיוון של אימוץ מהיר של תרופות ביוסימילאריות בישראל עשוי להוות פתרון ישים וקל להרחבת המקורות לתקציב עדכון סל הבריאות (בהיקף של 600 מיל' ₪ ומעלה) מבלי שהאוצר יזדקק להוסיף תקציב משלו לכך.
הטיעונים שלנו מבוססים על 3 נקודות:
1. על הרופאים להעריך את אפשרות השימוש בתרופות הביוסימילאריות באותו אופן שבו נעשה כיום שימוש בתרופות גנריות, כפי שקורה באמת כיום במספר רב של מדינות מערביות עם רפואה מתקדמת, הן עבור מטופלים נאיביים לטיפול ביולוגי והן עבור מטופלים הנמצאים כבר תחת טיפול ביולוגי, בכל ההתוויות הקיימות לרבות סרטן.
2. שיעורי הפחתת העלות הפוטנציאלים מאימוץ תרופות ביוסימילאריות הם גבוהים מאוד, כ-50%-80% מהעלות הנוכחית של תרופות המקור הביולוגיות. בישראל, שבה שוק התרופות כידוע ריכוזי מאוד יש אפשרות להשגת שיעורי הפחתה מקסימליים.
3. חיסכון אפשרי זה בעלויות הטיפול התרופתי מאפשר למשרד הבריאות להגדיר, באמצעות ועדת סל הבריאות, שתרופות ביולוגיות שמחירן לא יהיה קרוב לתרופות הביוסימילאריות שלהן , יוצאו מסל הבריאות (כלומר השימוש בהן יתאפשר רק במימון פרטי ולא דרך הקופות). כחלופה לכך משרד הבריאות יכול לאשר לקופות להוציא מהסל שלהן את התרופות הביולוגיות היקרות שאינן מעדכנות מחיריהן לרמה של הביוסימילאריות. יש להדגיש , שבשני המקרים השינוי דורש אישור החלפת תרופות מקור ביולוגיות לביוסימילאריות למטופלים בתרופות ביולוגיות מקוריות כיום.
הערת המערכת: לכאורה לא אמורה הייתה להיות מניעה גם כיום לכך שקופות החולים יתייחסו לתרופות הביוסימילאריות בדיוק כפי שהן עושות זאת מצוין ובאופן יעיל מאוד עם תרופות גנריות. עם זאת נראה כי בשל גישה שונה של המערכת הרפואית לביוסמיליאר, והסטטוס שלהן במשרד הבריאות – זה עדיין לא קורה. לכן למאמר זה יש חשיבות רבה להערכתנו ואנו מקווים שיעורר דיון בסוגייה בקרב כל הגורמים הקשורים לנושא.
Biosimilar should be thought of by physicians as generics and are indeed treated that way by medically-advanced countries. This article addresses medical professionals and we assume readers are familiar with the difference between drugs based on organic molecules and drugs based primarily on long peptide chains proteins (we will refer to those here as ‘biologics’). We also assume readers are familiar with the idea that organic molecules can be replicated accurately by companies other than the innovator, leading to ‘generics’ and biologic drugs can be replicated less accurately and these copies are referred to as biosimilars.
The argument is whether biosimilars should be treated as generics. The inventors of these drugs argue they cannot and physicians, being cautious, tend to be skeptical of the replicas. This caution is misplaced. Here are the three main reasons why – building from weakest to strongest
(i) The argument for fundamental differences between replicating small molecules and replicating ‘biologics’ is exaggerated. It is a simplification of much more complex reality. Those who follow manufacturing of drugs closely will attest that generic drugs differ slightly from their corresponding innovator drugs. Further, each batch of innovator-made biologic product is slightly different from other batches made by the same manufacturer and changes tend to expand over time (‘product drift’). The key point is that differences between humans (size, metabolism, etc.) far exceeds the small differences between drugs and their replicas (small molecules or biologics).
(ii) Biosimilar requirements for approval are exceedingly stringent. In setting the requirement for biosimilars both FDA and EMA (the main regulatory bodies reviewing biosimilars) were well-aware of all the risks associated with copying biological drugs. They were also lobbied extensively by the innovative companies (we attended one FDA meeting where innovator company staff argued approval of biosimilars will ‘kill patients). The staff at the regulators has strong interest against putting deficient products on the market. They personally gain nothing from approval, but can lose their career if approved products cause damage. As result, the standard set by the regulators are very high. In short, Israeli physicians should be confident that the product have behind them both the data and reputation of the foremost leading experts in the world on replicating molecules (If you trust FDA judgement on approving novel drug, why not trust it on replicating existing drug). A supporting point is that biosimilars are manufactured by many of the innovator companies are also engaged in developing and making innovator products – Novartis, Pfizer, Amgen, Biogen. They seem to be convinced that biosimilars can be safe and effective (and are putting their reputation and money at risk).
(iii) In practice, biosimilars have been proven safe and effective. Europe has been early in approving biosimilars (10 years before the US). After a slow start, biosimilars adoption have begun to accelerate with new entries capturing majority of the market within a year or two (Exhibit 1). The faster adoption has been primarily within more medically advanced countries – for example Germany, UK, Norway and Denmark. The adoption in all these countries included requiring existing patients to change from the innovator to the biosimilar products. Norway has been most aggressive, switching its entire population between drugs based on pricing (Exhibit 2). The switches had no negative clinical impact. This has been closely tracked by the countries involved (notably UK and Denmark). Speaking off the record, government staff noted to us the innovators mounted scare campaign including recruiting local clinical experts to explain how some sensitive populations may be hurt. None of this has actually happened. In short, theoretical argument aside – in practice, there has now been several, very large, switches from innovator products to biosimilars with years of follow on. No negative impact has been noted despite extensive attention.
Biosimilars should be adopted for all patients (new and currently on branded drugs) and all indications. Early in the formation of the biosimilar industry there was an extensive debate regarding the extent of biosimilar use. (i) should approvals include all indications or just those studied clinically and (ii) should both new patients and existing patients already on innovative drugs receive the biosimilars or just new patients. These issues have been extensively studied and, as in the generic case, biosimilars are viewed as appropriate for extrapolation for all indications and switching from innovators to biosimilar drugs does not cause negative effects. There are specific cases however, where the regulators require (again, as in the generic case) additional studies to ensure extrapolation and switching are appropriate.
- Starting with the ‘hypothetical’ arguments. With regard to extrapolation, Biosimilars are approved based on their similarity to the innovator and not their direct efficacy in clinical trials (the innovators have already done that). That similarity between the innovator and biosimilar holds for all indications and all patients for well-designed products. There are ‘special cases’ where there are differences in mechanism of action of the same drugs in different indications or patient populations. In these cases, further studies of the biosimilars are required to ensure the action is similar across indications. With regard to switching patients, the logic is similar. In most cases there is limited concerns. There are cases where there could be higher risk (at least in theory) when patients switch between back and forth between very similar drugs. In these cases, additional testing is required to ensure that this does not happen.
- Second, from a regulatory perspective, both EMA and FDA have considered the extrapolation and switching risk points. They have done so in great details and after extensive lobbying by the innovators. Both regulatory agencies have established specific testing requirements to ensure there is no difference in the efficacy of action between indications and specifically look at the impact of switching patients from the innovator drugs to biosimilars. Thus, products approved by both FDA and EMA for all indications should be viewed as having addressed these concerns. EMA in particularly published papers where they explain their approach and argue extrapolation it is appropriate. In short, the FDA and EMA answer to the extrapolation and switching arguments is that there is scientific way to ensure extrapolation of indication and patient switches from innovator to biosimilar are safe and effective. The appropriate scientific data is generated as part of the approval process to ensure that and that data is evaluated by the best experts in the field to ensure approved only if stringent criteria are met.
- Last and strongest point is that switching patients has been extensively studied post approval and is broadly practiced in European countries (again UK, Denmark, Norway, Germany are the pioneers). There is no evidence in clinical practice that switching patients previously using the innovator causes reduction in efficacy or increase in side effects (especially immunogenicity). Similarly, there was no differences observed in the efficacy and safety of biosimilar products across indications.
The discounts available from use of biosimilars are very large. Here we make three points: (i) biologic drugs sold by innovator are exceedingly profitable today and their price can come down materially; (ii) both biosimilars and innovators give very large discounts when biosimilars were introduced to the market; (iii) the share of products facing biosimilars near term is large and adoption of biosimilars will materially impact Israel’s cost of drugs
One of the fallacies of drug prices is that cost of making biological drugs is very high. This was the case 30 years ago, but the price has since dropped materially as the industry gained experience. The price of making most biologic drugs (mostly antibodies) is now below $100 per gram. This makes the innovator biologics, sold mostly at above $5000 per gram operate with 98% gross margin (for every shekel of revenue, only two agorot are used for manufacturing). Thus, if the price falls by 80%, the manufacturer makes only 20 agorot. Since manufacturing cost is still 2 agorot, the margin is ‘only’ 90%
This is not a theoretical argument. While the discounts provided after biosimilars introduction are generally not disclosed, there were instances when they were made public. Norway, for example, made public it obtained 80%+ discount on Enbrel biosimilar (vs. price it paid for the brand ahead of biosimilar entry); the UK stated it obtained ‘close to 80%’ discount on biosimilar Humira. We can also estimate the average discount provided in Europe from company reported sales and volume estimates. This discount is roughly 50%. This average price includes countries which do no have an effective mechanism to drive biosimilar adoption. We note this information is not controversial – i.e. the innovators agree this is typical discount.
How much can Israel save? Israel spends roughly 10 Billion Shekels per year on drugs (which is ~10% of the health budget which is in turn, 7.5% of Israel’s GDP). We do not have estimates of the cost of specific drugs in Israel, but based on global markets, the first wave of drugs exposed to biosimilar competition totaled (Humira, Enbrel, Remicade, Avastin, Herceptin, Rituxan, Neulasta and Insulin) somewhere about 10%-15% of total drug costs. Assuming similar ratios in Israel and 50% price reduction, we arrive at 600M shekels as a starting estimate for Israel savings that can be achieved within one to two years. Further reductions should be expected later in the 2020-2030 period with additional classes of drugs facing biosimilar medicine (notable the anti VEG-F and anti PD(L)-1).
Israel needs to make relatively simple changes to take advantage of the biosimilar opportunity. The Israeli policy regarding biosimilars suffers from two major flaws. First, the policy in general limits entry of new drugs to the medicines basket at an estimated sum pre-fixed by the ministry of health. Once drugs are included, they are included ‘for good’. There is no established mechanism to remove drugs for the basket. The exception is with generics where the payers (Kupot Holim) are allowed to choose between the brand and its generics. Second, the Israeli policy found here (link) specifically does not allow removing patients from the innovator drug and replacing it with the biosimilar. Respectfully, this is a wrong, wasteful policy. It is contrary to scientific evidence to date, the judgement of regulators and health care payers and the experience to date in the more medically advanced countries. It not only directly limits the adoption and potential savings from biosimilars, but also educates a generation of physicians that biosimilars are not ‘functional generics’ to their reference molecule.
We propose one of two solutions.
- In the more aggressive solution, the ministry of health changes the policy to enable exclusion of the innovator drugs (and the biosimilars) from the medicines basket, unless they provide a target price which is equivalent to those in the ‘single payer’ countries like Norway, Denmark or the UK. The ministry can go further and limit the number of products of given molecule available in the based (so to exclude one or more). This direct negotiation model will yield the highest savings
- In the second mechanism, the ministry changes policy so to allow the payers (Kupot Holim) to make their own choice between the products as they do for generics and the payers choose products based on lowest price available. The ministry can further incentivize the payers to seek lower prices by limiting the reimbursement amount to its own calculation of what they should be able to achieve.
- This approach may be easier operationally, but will split Israel’s buying power and this result in higher prices.
In either case, it is critical the change will include both existing and new patients (which we discussed above is medically appropriate). In other markets where biosimilars were offered only to new patients biosimilars failed to gain share and prices did not go down materially. This is due to several reasons. First, doubt by physicians that biosimilars are equally good – if they are, why are they not appropriate to existing patients? (and the innovators market on this point). Second, medical providers (clinics, hospitals, physicians) tend to standardize on single product for single use. Splitting creates complexity and as long as they do not have to or gain financially, they stick with one product. If significant share of patients must use the innovator product, they typically stay with innovator. Third, because biosimilar providers have less to gain, they give lower rates of discounts. The innovators, who are guaranteed share of each payer contract provide even less discounts. It usually ends up with the innovator giving 10% discount to keep the entire contract.
The comments above are written with the decision makers in mind. The physician reader of this article would naturally be a bit skeptical about this entire approach. Adoption of biosimilars may save money for the ‘system’. However, how would (my) patients benefit? The same question applies to patients’ groups. We note patient groups and professional societies have been used extensively in lobbying effort by innovators.
We point to three main arguments here.
- First, all payers ration expensive drugs. This is done through limitation on patient eligibility to drugs. In countries who adopted biosimilars, we have seen an acceleration of use of drugs once biosimilars became available. For example, the use of Enbrel and its biosimilars in Europe has grown at 10% per year since biosimilars were introduced (vs. close to no growth in prior years). That is, once costs came down, payers were less restrictive in their rationing policies. A positive for the patients.
- Second, Israeli medicine is slow to adopt new drugs, in part because it starts from fixed budget and old drugs are automatically in. There is now a significant wave of expensive drugs making its way through clinical development (Oncology, RNA-based and gene therapy). Lower cost of older drug will ‘clear budgetary space’ for new therapy to be adopted sooner.
- Third, there is a room to consider direct patient benefit from switching to biosimilars, at least in the early transition years. This could be in the form of cost reduction (lower premium or out of pocket charges) or added services (e.g. home infusion, rather than facility).
In conclusion, Biosimilar drugs approved by the FDA and EMA are as safe and as effective as the drugs they replicate. They are being rapidly adopted in the countries where medicine is more advanced and provide discounts similar in magnitude to generic drugs. Given the number and size of drugs exposed to first wave biosimilars, Israel stands to save roughly 10%+ of total drug costs if it makes relatively simple policy changes allowing it to create an auction where it chooses between innovator product and its biosimilar based on their price. The savings will enable less rationing of existing drugs and more rapid adoption of new drugs. Fear of change is the main adversary.
למצגת עם מס' גרפים המציגים מגמות נתח שוק של ביוסימילאר מול תרופות מקור במס' מדינות