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New drugs: where did we go wrong and what can we do better?

BMJ 2019; 366 doi: (Published 10 July 2019) Cite this as: BMJ 2019;366:l4340

Rapid Response:

Re: New drugs: where did we go wrong and what can we do better?

Did we really go wrong?

Regulators assess the quality of medicines, and authorise them only when benefits seen so far outweigh the risks. Thereafter HTA experts determine where the medicines fits in the therapeutic arsenal and the patient population for whom the product can be reimbursed or covered. HTA constantly explained these are two different roles, and yet authors tend to conclude regulators are not considering the added therapeutic value of new products. Well, this is precisely the role of HTA, not of regulators (with the exception of the Significant Benefit as defined by the Regulation on Orphan Medicinal Products 141/2000 article 3.1 b).

While acknowledging that not all authorised medicines find their role in the armamentarium against diseases, EURORDIS disagrees with the authors’ opinion that regulators fail to focus on the needs of the patients when authorising medicines with minor benefit over existing options at the time of their authorisation.

In real life, treatment strategy trials, consensus conferences of experts, or real world evidence inform patients and doctors’ decisions on how to make the best use of authorised products, gaining experience and knowledge when more patients are treated after the authorisation. But for this to happen, the medicine has to be authorised in the first place, following the above mentioned regulatory assessment of quality, efficacy and safety.

A major risk all patients are facing is when regulators do not authorise a yet effective medicine. Beate Wieseler and colleagues tend to ignore that industry and regulators need to accelerate the development and the evaluation of medicines in the interest of patients. They evaluate if a medicine can work in the context of a clinical trial, i.e. if the benefits can outweigh the risks. If the case, then the product can be authorised and the medical field can learn how to best use it. It is not the scope of regulators to determine the full clinical added-value of medicines. A new medicine cannot be compared to all existing options in extenso otherwise their development would last for ever.

Here are some examples where patients and public health benefited from medicines that were authorised with apparently only minor benefit over existing treatments, if any:

• At the time they were placed on the market, none of the four anti-tuberculosis treatments used alone, i.e. rifampicin, isoniazid, pyrazinamide or ethambutol had a considerable or major added benefit compared to standard of care or compared to each other. Used one by one, they had no effect. Only when doctors started to use them in combination therapies (bi or triple therapy) and because they had been placed on the market, then patients could be cured and the bacteria eradicated from their body.

• Same for anti-HIV treatments, where none of them used individually had sustainable clinical benefit in terms of mortality or morbidity in the first period 1986-2000. Only years after their authorisation, HIV doctors started to combine them, using the latest information they had on HIV resistance profile to construct potent regimen. The second authorised reverse transcriptase inhibitor, didanosine, was more potent to increase the number of CD4 cells compared to zidovudine, but with a difference of only 11 cells per mm3 in favour of didanosine. Nothing clinically relevant, but thereafter all patients could start combining the two, and this had a clinical effect.

• In cancer, most of the progresses are step-by-step mortality gains of a few percent, where each new product can add something, even if minor, to available options. Mortality from all cancers in the EU declined annually by 1.5% in men since 1990 and by 0.8% in women. Post-authorisation clinical research using observational studies and treatment protocol comparisons helped oncologists to determine which different combination therapies were the most effective.

• In rare diseases, some products are authorised with a modest effect size or limited efficacy data, and high uncertainty, due to the difficulties to recruit adequate numbers of trial subjects. But, used in clinical practice thereafter, specialist doctors learn to distinguish which patients can benefit the most and post-authorisation studies can generate additional evidence.

• Many medicines find a new medical use years after having been placed on the market. Off-label use is s source of medical progress. Drugs can only be repositioned if they are authorised in the first place. A minor added benefit is not a reason to reject a new medicine from the market, as long as it outweighs the risks.

The European legislator is certainly concerned by patients who have no treatment option. Regulation 726/2004 article 14a.2 is a response to the situation of patients who have no satisfactory methods of diagnosis, prevention or treatment. For those patients, it is of utmost importance to make new products available. For other, research can continue to increase the treatment options. This is the sense of compassionate use schemes, conditional authorisation and /or adaptive authorisation. The role of HTA is then to determine which treatment can help the most, i.e. their relative efficacy and how much society is willing to invest. But a prerequisite for HTA to do their job is to have the medicines authorised for human use in the first place. Nowadays regulators and HTA experts propose joint scientific advice to increase chances that adequate data are submitted both to regulator and to HTA bodies at a later stage.

Competing interests: No competing interests

18 July 2019
François Houÿez
Director of Treatment Information and Access
Virginie Hivert (Therapeutic Development Director - Eurordis)
European Organisation for Rare Diseases (Eurordis)
96 rue Didot, 75014 Paris - France